doxorubicin

vincristine

etoposide

cisplatin

melphalan

Confluence-dependent resistance in human colon cancer cells: role of reduced drug accumulation and low intrinsic chemosensitivity of resting cells.  In vitro sensitivity of HT29 human colon cancer cells to doxorubicin ( DXR ) , vincristine ( VCR ) , etoposide ( VP16 ) , cisplatin ( CDDP ) , melphalan ( L-PAM ) and 5-fluorouracil ( 5FU ) was markedly reduced when cell-culture density increased . For some drugs, confluence-dependent resistance (CDR) was partly due to decreased intracellular drug accumulation; the ratio of mean intracellular drug content of non confluent to confluent cells (NC/C) was 2.5 for DXR, 4.1 for VCR and 7.4 for VP16. Altered drug penetration with confluence could be related to decrease of plasma membrane fluidity as measured by the fluorescence polarization method. Reduction of drug intracellular accumulation was nil or weak for L-PAM (NC/C = 1.0), CDDP (NC/C = 1.2) and 5 FU (NC/C = 1.8). Even if drug concentration was adjusted in culture medium to produce similar intracellular drug content in confluent and non confluent cells, higher intrinsic resistance of confluent cells was still evidenced for DXR and VP16 but not for VCR, the only agent without direct interaction with DNA. DXR- and VP16-induced DNA breakage was also less important in confluent than in non-confluent cells. CDR appeared closely related to an increased proportion of non-cycling cells at confluence, as demonstrated by flow cytometry, expression of nuclear antigen recognized by Ki67 MAb and expression of topoisomerase II. CDR is probably a major factor in the poor sensitivity of colorectal adenocarcinomas to chemotherapy.


oxaliplatin

fluorouracil

ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy . To test the hypotheses of whether the relative mRNA expression of the thymidylate synthase (TS) gene and the excision cross-complementing (ERCC1) gene are associated with response to and survival of fluorouracil (5-FU)/oxaliplatin chemotherapy in metastatic colorectal cancer. ### Patients And Methods Patients had progressive stage IV disease after unsuccessful 5-FU and irinotecan chemotherapy. All patients were evaluated for eligibility for a compassionate 5-FU/oxaliplatin protocol. cDNA was derived from paraffin-embedded tumor specimens to determine TS and ERCC1 mRNA expression relative to the internal reference gene beta-actin using fluorescence-based, real-time reverse transcriptase polymerase chain reaction. ### results The median TS gene expression level from 50 metastasized tumors was 3.4 x 10(-3) (minimum expression, 0.18 x 10(-3);maximum expression, 11.5 x 10(-3)), and the median ERCC1 gene expression level was 2.53 x 10(-3) (minimum, 0.0; maximum, 14.61 x 10(-3)). The gene expression cutoff values for chemotherapy nonresponse were 7.5 x 10(-3) for TS and 4.9 x 10(-3) for ERCC1. The median survival time for patients with TS <or= 7.5 x 10(-3) (43 of 50 patients) was 10.2 months, compared with 1.5 months for patients with TS greater than 7.5 x 10(-3) (P < .001). Patients with ERCC1 expression <or= 4.9 x 10(-3) (40 of 50 patients) had a median survival time of 10.2 months, compared with 1.9 months for patients with ERCC1 expression greater than 4.9 x 10(-3) (P < .001). A TS of 7.5 x 10(-3) segregated significantly into response, stable disease, and progression (P = .02), whereas the association between ERCC1 and response did not reach statistical significance (P = .29). ### conclusion These data suggest that intratumoral ERCC1 mRNA and TS mRNA expression levels are independent predictive markers of survival for 5-FU and oxaliplatin combination chemotherapy in 5-FU-resistant metastatic colorectal cancer. Precise definition of the best TS cut point will require further analysis in a large, prospective study.


pamidronate

thalidomide

Combination of pamidronate and thalidomide in the therapy of treatment-resistant multiple myeloma. Bisphosphonates inhibit the activity of osteoclasts and demonstrate antitumor effect, involving induction of plasmocyte apoptosis, blocking of angiogenesis, stimulation of Tgd lymphocytes and inhibition of metalloproteinases. Bisphosphonates combined with thalidomide, a drug possessing confirmed anti-myeloma activity, seem to have potential favorable effect in patients with treatment-resistant multiple myeloma with advanced osteolytic lesions. ### Material Methods 13 patients with treatment-resistant multiple myeloma with advanced osteolytic lesions received combined pamidronate and thalidomide therapy. All the patients underwent detailed clinical and laboratory control once a month. pamidronate was used at 90 mg i.v. dose administered at 4-week intervals, and thalidomide at doses escalated from 200 mg/d in the first week to 400 mg/d after 3 weeks of the therapy. The mean duration of treatment was 12 weeks with a range of 3 to 36 weeks. ### results 7 patients ( 53 % ) receiving pamidronate and thalidomide therapy demonstrated good response involving at least 25 % reduction of monoclonal protein levels in comparison with baseline . All these patients reported improvement of osteodynia symptoms, and 3 of them - their complete regression. 70% patients experienced side effects (dizziness, constipation, somnolence, polyneuropathy) due to thalidomide administration ### conclusions Good response to combined pamidronate and thalidomide therapy can be expected in at least 50% of patients with treatment-resistant multiple myeloma with advanced osteolytic lesions.


doxorubicin

mitomycin

cisplatin

etoposide

In vitro chemosensitivity of human pancreatic cancer cell lines. These results show that eight pancreatic cancer cell lines are broadly sensitive to CDDP, and that chemotherapy for pancreatic cancer may improve the prognosis by more effective drug delivery to cancer cells. ### background Chemotherapy for pancreatic cancer does not satisfactorily improve prognosis. The efficacy of chemotherapy depends on choosing sensitive anticancer drugs. ### methods The in vitro chemosensitivity of eight human pancreatic cancer cell lines was investigated. Growth inhibition was measured by 3H-thymidine incorporation assays for doxorubicin hydrochloride ( ADM ) , mitomycin C ( MMC ) , cisplatin ( CDDP ) , and etoposide ( VP-16 ) , and by Alamar Blue assay for ( AB assay ) 5-fluorouracil ( 5-FU ) . The cells were exposed to ADM, MMC, CDDP, and VP-16 for 2 h, and 5-FU for 72 h. From the dose-response curves, the 50% growth inhibition (IC50) level for each drug was estimated. ### results The IC50 after 2 h of exposure of each of the eight kinds of cell lines to each anticancer drug ranged from 0.12-8.2 micrograms/mL for ADM, 0.066-25 micrograms/mL for MMC, 0.57-7 micrograms/mL for CDDP, 0.68-300 micrograms/mL for VP-16. IC50 after 72 h of exposure to 5-FU ranged from 1.8-23 micrograms/mL.


moxifloxacin

pyrazinamide

amikacin

ethionamide

Sterilizing activity of second-line regimens containing TMC207 in a murine model of tuberculosis. The sterilizing activity of the regimen used to treat multidrug resistant tuberculosis (MDR TB) has not been studied in a mouse model. ### Objective And Methods Swiss mice were intravenously inoculated with 6 log10 of Mycobacterium tuberculosis (TB) strain H37Rv, treated with second-line drug combinations with or without the diarylquinoline TMC207, and then followed without treatment for 3 more months to determine relapse rates (modified Cornell model). ### measurements Bactericidal efficacy was assessed by quantitative lung colony-forming unit (CFU) counts. Sterilizing efficacy was assessed by measuring bacteriological relapse rates 3 months after the end of treatment. ### Main Results The relapse rate observed after 12 months treatment with the WHO recommended MDR TB regimen (amikacin, ethionamide, pyrazinamide and moxifloxacin) was equivalent to the relapse rate observed after 6 months treatment with the recommended drug susceptible TB regimen (rifampin, isoniazid and pyrazinamide). When TMC207 was added to this MDR TB regimen, the treatment duration needed to reach the same relapse rate dropped to 6 months. A similar relapse rate was also obtained with a 6-month completely oral regimen including TMC207 , moxifloxacin and pyrazinamide but excluding both amikacin and ethionamide . ### conclusions In this murine model the duration of the WHO MDR TB treatment could be reduced to 12 months instead of the recommended 18-24 months. The inclusion of TMC207 in the WHO MDR TB treatment regimen has the potential to further shorten the treatment duration and at the same time to simplify treatment by eliminating the need to include an injectable aminoglycoside.


Propranolol

Pembrolizumab

Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma : Safety , Tolerability , and Preliminary Evidence of Antitumor Activity . Increased β-adrenergic receptor (β-AR) signaling has been shown to promote the creation of an immunosuppressive tumor microenvironment (TME). Preclinical studies have shown that abrogation of this signaling pathway, particularly β2-AR, provides a more favorable TME that enhances the activity of anti-PD-1 checkpoint inhibitors. We hypothesize that blocking stress-related immunosuppressive pathways would improve tumor response to immune checkpoint inhibitors in patients. Here, we report the results of dose escalation of a nonselective β-blocker (propranolol) with pembrolizumab in patients with metastatic melanoma. ### Patients And Methods A 3 + 3 dose escalation study for propranolol twice a day with pembrolizumab (200 mg every 3 weeks) was completed. The primary objective was to determine the recommended phase II dose (RP2D). Additional objectives included safety, antitumor activity, and biomarker analyses. Responders were defined as patients with complete or partial response per immune-modified RECIST at 6 months. ### results Nine patients with metastatic melanoma received increasing doses of propranolol in cohorts of 10, 20, and 30 mg twice a day. No dose-limiting toxicities were observed. Most common treatment-related adverse events (TRAEs) were rash, fatigue, and vitiligo, observed in 44% patients. One patient developed two grade ≥3 TRAEs. Objective response rate was 78%. While no significant changes in treatment-associated biomarkers were observed, an increase in IFNγ and a decrease in IL6 was noted in responders. ### conclusions Combination of propranolol with pembrolizumab in treatment-naïve metastatic melanoma is safe and shows very promising activity. propranolol 30 mg twice a day was selected as RP2D in addition to pembrolizumab based on safety, tolerability, and preliminary antitumor activity.


Iohexol

iodixanol

A novel contrast-induced acute kidney injury model based on the 5/6-nephrectomy rat and nephrotoxicological evaluation of iohexol and iodixanol in vivo. Contrast-induced acute kidney injury (CI-AKI) is a serious complication in patients after administration of iodinated contrast media. Proper animal models of CI-AKI can help understand the mechanisms involved and prevent the disorder. We used the 5/6-nephrectomized (NE) rat to develop a CI-AKI model and to evaluate differences in the toxic effects on the kidney between iohexol and iodixanol. We found that six weeks after ablative surgery was the preferred time to induce CI-AKI. We compared multiple pretreatment plans and found that dehydration for 48 hours before iodixanol (320, 10 mL/kg) administration was optimal to induce CI-AKI in the 5/6 NE rats. Compared with iodixanol, iohexol induced a significantly greater reduction in renal function, severe renal tissue damage, intrarenal hypoxia, and apoptotic tubular cells. Iohexol and iodixanol resulted in similarly marked increases in levels of inflammation and oxidative stress . In summary, the 5/6 NE rat combined with dehydration for 48 hours is a useful pretreatment to establish a novel and reliable CI-AKI model. iohexol induced more severe CI-AKI than iodixanol in this model.


vinorelbine

paclitaxel

Synergism of cytotoxic effects of vinorelbine and paclitaxel in vitro. Empiric combinations of vinca alkaloids with taxanes have been recently used in clinical oncology. To enhance the activity of these two classes of agents, we evaluated the sequence and duration of exposure, looking for synergistic effects. Cell lines DU 145, PC 3, LnCaP, LL 86, MCF7wt, and MCF7/ADR (NCI/ADR-RES) were incubated with varying concentrations of paclitaxel or vinorelbine. Cytotoxicity was evaluated by a semiautomated MTT (3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide) method. Synergism or antagonism of these two agents either sequentially or in combination was determined by median effect analysis. Prolonged exposure of cells to either drug enhanced cytotoxic effect. Synergism or antagonism with vinorelbine and paclitaxel were both sequence dependent and cell line specific. In the case of MCF7wt, synergism was seen when a 48-hr exposure to vinorelbine preceded paclitaxel, whereas antagonism was noted when both agents were applied simultaneously or when the sequence was reversed. Concurrent vinorelbine and paclitaxel were synergistic in four of six cell lines when the exposure was extended to 96 hr but not for shorter durations of exposure. Sequential exposure of vinorelbine preceding paclitaxel or prolonged exposure to both agents concurrently needs to be tested clinically to determine whether the antitumor activity of this combination can be enhanced . In addition, these studies suggest concurrent administration of these two agents may lead to a less than optimal cytotoxic result.


doxorubicin

etoposide

Genotoxic effects of topoisomerase poisoning and PARP inhibition on zebrafish embryos. Topoisomerase poisons are known to stabilize covalent enzyme-DNA intermediates forming covalent cleavage complexes, which are highly cytotoxic especially for dividing cells and thus, make topoisomerases targets for cancer therapy. Topoisomerases have been extensively studied in mammalian model systems, whereas in other vertebrate models including zebrafish, they still remain less characterized. Here we show similarities in the genotoxic effects of zebrafish and mammalian systems towards topoisomerase I (Top1) poisons and PARP inhibitor - olaparib. On the other hand we observed that topoisomerase II ( Top2 ) poisons ( doxorubicin and etoposide ) did not affect 1 day post fertilization embryo viability , however in cells isolated from Top2 drug treated embryos the formation of DNA cleavage complexes was observed by comet assay . We explain this by cellular drug uptake limitation in live zebrafish embryos versus unimpeded drug influx in cells isolated from Top2 poisons pre-treated embryos. We also demonstrate that EDTA facilitates the extraction of Top2 from zebrafish nuclei and recovers both, basal and Top2 poison induced DNA damage.


Sorafenib

Nivolumab

Favorable Response of Metastatic Hepatocellular Carcinoma to Treatment with Trans-arterial Radioembolization Followed by Sorafenib and Nivolumab . Trans-arterial radioembolization (TARE) with Y-90 microspheres is an endovascular, liver-directed therapy suitable for treatment of locally advanced hepatocellular carcinoma (HCC) often as a way to reduce tumor size and bridge patients to resection or liver transplant. Opdivo®, or nivolumab, a programmed cell death protein 1 (PD-1) inhibitor, is an immunotherapeutic drug approved in September 2017 for the treatment of HCC in patients who have received prior sorafenib. We report on a patient with hepatocellular carcinoma with right and left portal vein involvement, bony metastasis, and possible lung metastasis. The patient showed a significant response following consecutive treatment with TARE, sorafenib, and nivolumab. Our case suggests that TARE, sorafenib, and nivolumab may have a synergistic effect on the immune response to HCC.


procarbazine

lomustine

vincristine

Combined treatment modality for anaplastic oligodendroglioma and oligoastrocytoma: a 10-year update of a phase II study. To provide updated outcome data (10 years) of a Phase II study of combined surgery, postoperative radiotherapy, and adjuvant chemotherapy in patients with anaplastic oligodendroglioma and oligoastrocytoma. ### Methods And Materials In 23 adult patients , surgery , postoperative radiotherapy ( 60 Gy in 30 daily fractions within 6 weeks ) , and adjuvant modified chemotherapy ( procarbazine 60 mg/m(2 ) on Days 1 - 14 , lomustine 100 mg/m(2 ) on Day 1 , and vincristine 1.4 mg/m(2 ) [ maximum 2 mg ] on Days 1 and 8) were administered every 6 weeks for up to six cycles or until progression occurred . ### results The median follow-up was 116 months for all patients. The median survival time was 118 months, and the 5-year and 10-year survival rate was 57% and 47%, respectively. The median time to tumor progression was 78 months, with a 5-year and 10-year progression-free survival rate of 52% and 39%, respectively. Gender, age, Karnofsky performance status, location, and histologic type did not influence survival. Patients with tumors <or=4 cm did better than those with tumors >4 cm (p = 0.0470), as did those with total tumor resection compared with those with subtotal tumor resection or biopsy only (p = 0.0024). Gender, Karnofsky performance status, location, and histologic type did not influence progression-free survival, but younger age (p = 0.0389), smaller tumor size (p = 0.0357), and more radical surgery (p = 0.0033) correlated positively with it. Acute high-grade (Grade 3 or worse) chemotherapy-related toxicity was mainly hematologic, with 3 patients (13%) experiencing acute Grade 4 toxicity. ### conclusion The results of this 10-year update confirmed that the trimodality approach is effective in patients with anaplastic oligodendroglioma and oligoastrocytoma.


nivolumab

dacarbazine

Effect of nivolumab on health-related quality of life in patients with treatment-naïve advanced melanoma: results from the phase III CheckMate 066 study. nivolumab has shown significant survival benefit and a favorable safety profile compared with dacarbazine chemotherapy among treatment-naïve patients with metastatic melanoma in the CheckMate 066 phase III study. Results from the health-related quality of life (HRQoL) analyses from CheckMate 066 are presented. ### Patients And Methods HRQoL was evaluated at baseline and every 6 weeks while on treatment using the European Organisation for Research and Treatment of Care (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and the EuroQoL Five Dimensions Questionnaire (EQ-5D). Via a multi-step statistical plan, data were analyzed descriptively, cross-sectionally, and longitudinally, adjusting for baseline covariates, in patients having baseline plus ≥1 post-baseline assessment. ### results Baseline-adjusted completion rates for all HRQoL questionnaires across treatment arms were 65% and 70% for dacarbazine and nivolumab, respectively, and remained similar throughout treatment. The mean baseline HRQoL scores were similar for patients treated with nivolumab and dacarbazine. Baseline HRQoL levels with nivolumab were maintained over time. This exploratory analysis showed a between-arm difference in favor of nivolumab on the EQ-5D utility index and clinically meaningful EQ-5D improvements from baseline at several time points for patients receiving nivolumab. Patients treated with nivolumab did not show increased symptom burden as assessed by the EORTC QLQ-C30. No HRQoL change was noted with dacarbazine patients up to week 43, although the high attrition rate after week 13 did not allow any meaningful analyses. Patients receiving nivolumab deteriorated significantly later than those receiving dacarbazine on several EORTC QLQ-C30 scales and the EQ-5D utility index. ### conclusions In addition to prolonged survival , these exploratory HRQoL results show that nivolumab maintains baseline HRQoL levels to provide long-term quality of survival benefit , compared with dacarbazine in patients with advanced melanoma .


durvalumab

tremelimumab

A phase 1a/1b trial of CSF-1R inhibitor LY3022855 in combination with durvalumab or tremelimumab in patients with advanced solid tumors. Background LY3022855 is a recombinant, immunoglobulin, human monoclonal antibody targeting the colony-stimulating factor-1 receptor. This phase 1 trial determined the safety , pharmacokinetics , and antitumor activity of LY3022855 in combination with durvalumab or tremelimumab in patients with advanced solid cancers who had received standard anti-cancer treatments . Methods In Part A (dose-escalation), patients received intravenous (IV) LY3022855 25/50/75/100 mg once weekly (QW) combined with durvalumab 750 mg once every two weeks (Q2W) IV or LY3022855 50 or 100 mg QW IV with tremelimumab 75/225/750 mg once every four weeks. In Part B (dose-expansion), patients with non-small cell lung cancer (NSCLC) or ovarian cancer (OC) received recommended phase 2 dose (RP2D) of LY3022855 from Part A and durvalumab 750 mg Q2W. Results Seventy-two patients were enrolled (median age 61 years): Part A = 33, Part B = 39. In Part A, maximum tolerated dose was not reached, and LY3022855 100 mg QW and durvalumab 750 mg Q2W was the RP2D. Four dose-limiting equivalent toxicities occurred in two patients from OC cohort. In Part A, maximum concentration, area under the concentration-time curve, and serum concentration showed dose-dependent increase over two cycles of therapy. Overall rates of complete response, partial response, and disease control were 1.4%, 2.8%, and 33.3%. Treatment-emergent anti-drug antibodies were observed in 21.2% of patients. Conclusions LY3022855 combined with durvalumab or tremelimumab in patients with advanced NSCLC or OC had limited clinical activity, was well tolerated. The RP2D was LY3022855 100 mg QW with durvalumab 750 mg Q2W. ClinicalTrials.gov ID: NCT02718911 (Registration Date: May 3, 2011).


vildagliptin

voglibose

Pharmacokinetic and pharmacodynamic interaction of vildagliptin and voglibose in Japanese patients with Type 2 diabetes . To assess the extent of pharmacokinetic and pharmacodynamic interaction between vildagliptin, a potent and selective inhibitor of dipeptidyl peptidase IV (DPP-4) enzyme, and voglibose, an α-glucosidase inhibitor widely prescribed in Japan, when coadministered in Japanese patients with Type 2 diabetes. ### methods In this open-label, randomized, 3-treatment, 3-period and 6-way crossover study, 24 Japanese patients with Type 2 diabetes received 50 mg vildagliptin twice daily; 50 mg vildagliptin twice daily co-administered with 0.2 mg voglibose three times daily; or 0.2 mg voglibose three times daily for 3 days in each period. Plasma concentrations of vildagliptin, DPP-4, glucagon-like peptide-1 (GLP-1), glucose, insulin, and glucagon were determined from blood samples collected at steady state. ### results Exposure to vildagliptin 50 mg (area under the concentration-time curve from 0 to 12 hours (AUCτ,ss)) and maximum plasma concentration at steady state (Cmax,ss) was reduced by 23% and 34% respectively with co-administration of voglibose. The percentage of DPP-4 inhibition by vildagliptin remained unchanged when vildagliptin was given alone or co-administered with voglibose; maximum inhibition was 98.3 ± 1.4% (mean ± SD) for vildagliptin alone and 97.4 ± 1.1% with co-administration. Coadministration of vildagliptin and voglibose led to a greater increase in the active GLP-1 plasma concentration than did vildagliptin alone (geometric mean ratio 1.63 (90% CI, 1.30, 2.03), p = 0.0007). The combination of vildagliptin and voglibose also led to a significantly lower plasma glucose levels (p < 0.0001). ### conclusions Plasma vildagliptin levels were decreased when voglibose was co-administered, although DPP- 4 inhibition remained unchanged. Co-administration led to significantly better pharmacodynamic response compared with each treatment alone, including higher active GLP-1 and lower glucose levels. The results indicate that this coadministration may be beneficial in the clinical situation. vildagliptin and voglibose treatments, alone or when co-administered, were well tolerated in Japanese patients with Type 2 diabetes.


cisplatin

carboplatin

etoposide

doxorubicin

Neuroblastoma stem cells - mechanisms of chemoresistance and histone deacetylase inhibitors. Cancer stem cells (CSCs) form a small proportion of tumor cells that have stem cell properties: self-renewal capacity, the ability to develop into different lineages and proliferative potential. The interest in CSCs emerged from their expected role in initiation, progression and recurrence of many tumors. They are generally resistant to conventional chemotherapy and radiotherapy. There are two hypotheses about their origin: The first assumes that CSCs may arise from normal stem cells, and the second supposes that differentiated cells acquire the properties of CSCs. Both hypotheses are not mutually exclusive, as it is possible that CSCs have a diverse origin in different tumors. CD133 + cells ( CD133 is marker of CSC in some tumors ) isolated from NBL , osteosarcoma and Ewing sarcoma cell lines are resistant to cisplatin , carboplatin , etoposide and doxorubicin than the CD133- ones . Being resistant to chemotherapy, there were many attempts to target CSCs epigenetically including the use of histone deacetylase inhibitors. The diverse influence of valproic acid (histone deacetylase inhibitor) on normal and cancer stem cells was proved in different experiments. We have found an increase percentage of CD133+ NBL cells after their incubation with VPA in a dose that does not induce apoptosis. Further researches on CSCs and clinical application for their detection are necessary: (i) to define the CSC function in carcinogenesis, cancer development and their role in metastasis; (ii) to find a specific marker for CSCs in different tumors; (iii) to explain the role of different pathways that determine their behavior and (iv) to explain mechanisms of chemoresistance of CSCs.


gefitinib

erlotinib

afatinib

crizotinib

bevacizumab

Targeted therapies for treatment of non-small cell lung cancer--Recent advances and future perspectives. Non-small cell lung cancer (NSCLC) is one of the most deadly cancers worldwide, with poor prognosis once the disease has progressed past the point at which surgery is a viable option. Whilst chemotherapy has improved survival over recent decades, there is still great need for improvements in treatments for patients with advanced disease. Over the last decade, a variety of such drugs have received market approval for treating NSCLC, with a variety of others in the pipeline. Here, we review the development of targeted therapies for the treatment of advanced or metastatic NSCLC, including those already in clinical practice and those in early trials. The epidermal growth factor receptor ( EGFR ) inhibitors , gefitinib , erlotinib and afatinib ; the anaplastic lymphoma kinase ( ALK ) inhibitor , crizotinib ; and the anti-vascular endothelial growth factor receptor monoclonal antibody , bevacizumab , are already providing improved survival for patients with NSCLC . Moreover, the discovery of EGFR mutations and ALK rearrangements has enabled the identification of patients who are more likely to benefit from a specific drug. The recent approval of the immune checkpoint inhibitor nivolumab, along with the designation of alectinib and MPDL3280A as breakthrough therapies by the FDA, demonstrates how rapidly this area of research is expanding. Over the last decade there has been significant progress made in the treatment of advanced NSCLC, and the large and varied selection of drugs currently undergoing trials provide great promise for improving the prognosis of this highly prevalent and deadly form of cancer.


paroxetine

fluvoxamine

Contrasting actions of acute or chronic paroxetine and fluvoxamine on morphine withdrawal-induced place conditioning . The acute and chronic effects of paroxetine and fluvoxamine on naloxone withdrawal-induced place aversion in morphine dependent rats were investigated. Acutely administered fluvoxamine (25 mg/kg s.c. given 30 min prior to naloxone withdrawal pairing) and chronic daily paroxetine (10 mg/kg s.c.) coadministration with a morphine induction protocol, both attenuated morphine withdrawal place aversion. Conversely, acutely administered paroxetine (up to 25 mg/kg s.c.) or chronic daily fluvoxamine (10 mg/kg s.c.) coadministration with morphine did not modify subsequent withdrawal place aversion. Previous radioligand binding studies indicate that fluvoxamine has opioid-displacing properties. It is suggested therefore that acute fluvoxamine may have decreased withdrawal aversion, probably through serotonin and also, in part, via an opioid-like mechanism whereas chronic paroxetine decreased withdrawal aversion by a serotonergic mechanism, but it is not clear whether opioid systems play any role in the action of paroxetine.


sunitinib

bevacizumab

pazopanib

interferon-α

Advances in renal cell carcinoma treatment. The treatment of advanced renal cell carcinoma has been completely changed by the development of new therapeutic modalities during the past 3 years. In this time period six targeted agents have been approved for the treatment of advanced or metastatic disease. Phase 3 data support the use of sunitinib , bevacizumab plus interferon-α and pazopanib for patients with low and intermediate risk of clear-cell renal cell carcinoma . In the pivotal study of temsirolimus a significant longer overall survival compared with interferon-α in high-risk disease including non-clear-cell histology was observed. Patients pretreated with cytokines will benefit from sorafenib and pazopanib while everolimus has been shown to increase significantly progression-free survival after previous anti-angiogenesis therapy. In addition to these phase 3 data-based recommendations, several other factors have to be considered for treatment selection, for example, side effect profile and patients' comorbidities. Currently, the sequential use of the available targeted drugs and adjuvant treatment are the subject of ongoing clinical trials. However, medical treatment of renal cell carcinoma remains palliative and surgery remains the only curative approach in patients with localized, locally advanced and limited metastatic disease.


oxaliplatin

gemcitabine

[Oxaliplatin combined with gemcitabine in the treatment of patients with advanced non-small cell lung cancer]. The use of oxaliplatin is very little in the treatment of lung can- cer . This study is designed to find out the efficacy and toxicity of the combination of oxaliplatin and gemcitabine in the treatment of advanced non-small cell lung cancer ( NSCLC ) . ### methods There were 32 cases of advanced NSCLC patients who were treated with oxaliplatin 65mg/m² by intravenous infusion on the 1st and 8th days, and gemcitabine 800-1000mg/m² by intravenous infusion on the 1st and 8th days every 21 days. After 2 cycles the efficacy was evaluated. ### results There were 31 cases that could be evaluated. No complete response was observed and the overall response rate was 22.6% (7 partial response). The disease control rate was 71.0%. The median time to diease progression was 7 months and the median survival time was 14.5 months. The 1-year survival rate was 59.0% and 2-year survival rate was 45.8%. The main toxicities were myelosuppression and nausea and vomiting. ### conclusions The combination of oxaliplatin and gemcitabine is effective and well tolerated in the treatment of advanced NSCLC. The quality of life is little influenced and the regimen also can prolong the survival time in some patients.


cyclophosphamide

paclitaxel

Paclitaxel plus high-dose cyclophosphamide with G-CSF support in patients with relapsed and refractory aggressive non-Hodgkin's lymphoma. Based on the single-agent activity of both paclitaxel and cyclophosphamide in the treatment of non-Hodgkin's lymphoma (NHL), we conducted a phase II study to evaluate the efficacy of the combination of the two drugs in patients with refractory and relapsed aggressive NHL. All patients received 900 mg/m2 bolus of cyclophosphamide intravenously daily for 3 consecutive days with a concurrent infusion of 150 mg/m2 of paclitaxel over 72 h ( 50 mg/m2/d ) . 24 h after the completion of chemotherapy, patients received subcutaneous injections of 5 microg/kg of granulocyte-colony stimulating factor (G-CSF) daily until white cell count recovery. Treatment was repeated every 3 weeks. Patients who had at least a partial response (PR) after two courses continued to receive a maximum of four courses. Patients with responding disease were allowed to undergo high-dose chemotherapy followed by stem-cell/bone marrow transplantation if they were eligible. Of the 77 patients who were eligible for the study, 74 (96%) were evaluable for toxicity and treatment response. The overall response rate was 45% (95% CI 33-57%). Patients who received treatment after their disease relapsed from a complete response (CR) had an 81% response rate (38% CRs), whereas those with primary refractory disease had a 22% response rate. Toxicities of > grade 2 included alopecia (100%) and stomatitis (25%). Neutropenic fever of grade > 2 occurred after 18% of the courses, and platelet count of < or = 20 x 10(9)/l developed after 20% of the courses. Thus, the combination of paclitaxel plus high-dose cyclophosphamide is an effective new regimen in the treatment of refractory and relapsed NHL.


Rituximab

melphalan

Rituximab combined with a small dose of melphalan for a refractory follicular lymphoma patient . A 48-year-old male patient with follicular lymphoma, grade II, stage IV, was treated with CHOP, ESHAP and MACOP-B, resulting in partial remission. After 9 months, the disease progressed and several chemotherapy agents, including three courses of rituximab combined with etoposide, sobuzoxane or methotrexate, only resulted in a stable disease response. However, the fourth course of rituximab combined with a small dose of melphalan produced excellent results and the complete response continued for more than 15 months. It is possible that these two drugs may act synergistically.


mefloquine

azithromycin

Anti-bacterial activity of intermittent preventive treatment of malaria in pregnancy: comparative in vitro study of sulphadoxine-pyrimethamine, mefloquine, and azithromycin. Intermittent preventive treatment of malaria with sulphadoxine-pyrimethamine (SP) is recommended for the prevention of malaria in pregnancy in sub-Saharan Africa. Increasing drug resistance necessitates the urgent evaluation of alternative drugs. Currently, the most promising candidates in clinical development are mefloquine and azithromycin. Besides the anti-malarial activity, SP is also a potent antibiotic and incurs significant anti-microbial activity when given as IPTp - though systematic clinical evaluation of this action is still lacking. ### methods In this study , the intrinsic anti-bacterial activity of mefloquine and azithromycin was assessed in comparison to sulphadoxine-pyrimethamine against bacterial pathogens with clinical importance in pregnancy in a standard microdilution assay . ### results SP was highly active against Staphylococcus aureus and Streptococcus pneumoniae. All tested Gram-positive bacteria, except Enterococcus faecalis, were sensitive to azithromycin. Additionally, azithromycin was active against Neisseria gonorrhoeae. mefloquine showed good activity against pneumococci but lower in vitro action against all other tested pathogens. ### conclusion These data indicate important differences in the spectrum of anti-bacterial activity for the evaluated anti-malarial drugs. Given the large scale use of IPTp in Africa, the need for prospective clinical trials evaluating the impact of antibiotic activity of anti-malarials on maternal and foetal health and on the risk of promoting specific drug resistance of bacterial pathogens is discussed.


Pirfenidone

candesartan

Pirfenidone and candesartan ameliorate morphological damage in mild chronic anti-GBM nephritis in rats. The antifibrotic substance pirfenidone and the angiotensin II type I receptor antagonist candesartan cilexetil, given alone and in combination, were tested in rats with chronic anti-glomerular basement membrane glomerulonephritis (anti-GBM GN). ### methods Male Wistar rats with anti-GBM GN were treated for 8 weeks with candesartan (4 mg/kg body weight/day), pirfenidone (500 mg/kg body weight/day) or a combination of both drugs. One GN group received no treatment and untreated non-GN-rats were used as controls. Blood pressure and urinary protein excretion were measured after 3 and 7 weeks. Kidney histology was complemented by ultrastructural investigation and by quantification of collagen Ialpha mRNA. ### results The percentage of glomeruli with adsorption droplets in podocytes correlated well with the amount of proteinuria (r = 0.873, P<0.01) and was significantly lowered in rats treated with candesartan (8.3 vs GN 24.6%), pirfenidone (9.8%) and combined treatment (2.6%, P<0.05 vs candesartan alone). A comparable lowering was seen for segmental sclerosis (GN 11%, candesartan 0.7%, P<0.05 vs GN, pirfenidone 1.8%, P = 0.09 vs GN, candesartan/pirfenidone 0.1%, P>0.5 vs candesartan alone). Cortical collagen Ialpha mRNA expression was significantly decreased in all treatment groups. Ultrastructural investigation showed an amelioration of basement membrane alterations and podocyte damage in the treatment groups. candesartan caused significant blood pressure reduction and the effect was significantly enhanced by combination therapy after 3 weeks. Rats treated with pirfenidone showed blood pressure values similar to control rats. ### conclusion Pirfenidone has a beneficial effect on morphological changes in anti-GBM GN comparable with candesartan although with a trend to slightly better results with candesartan treatment. Moreover, our results suggest an additive effect of combination treatment.


Difluprednate

prednisolone

Difluprednate versus prednisolone acetate for inflammation following cataract surgery in pediatric patients : a randomized safety and efficacy study . PurposeTo evaluate safety and efficacy of difluprednate 0.05% ophthalmic emulsion for treatment of postoperative inflammation after cataract surgery in pediatric patients.MethodsThis was a phase 3B, multicentre, randomized, double-masked, active-controlled study of patients aged 0-3 years who underwent uncomplicated cataract surgery in one eye, with/without intraocular lens implantation. Patients were randomized to receive difluprednate 0.05% four times daily or prednisolone acetate 1% for 14 days post surgery, followed by tapering for 14 days. Safety included evaluation of adverse events. Primary efficacy was the proportion of patients with an anterior cell grade of 0 (no cells) at day 14; secondary efficacy was a global inflammation score.ResultsForty patients were randomized to each treatment group. Adverse drug reactions included corneal oedema (difluprednate 0.5%, n=1; prednisolone acetate 1%, n=0) and increased intraocular pressure or ocular hypertension (n=2/group). Mean intraocular pressure values during treatment were 2-3 mm Hg higher with difluprednate 0.05% compared with prednisolone acetate 1%; mean values were similar between groups by the first week after treatment cessation. At 2 weeks post surgery, the incidence of complete clearing of anterior chamber cells was similar between groups (difluprednate 0.05%, n=30 (78.9%); prednisolone acetate 1%, n=31 (77.5%). Compared with prednisolone acetate 1%, approximately twice as many difluprednate 0.05%-treated patients had a global inflammation assessment score indicating no inflammation on day 1 (n=12 (30.8%) vs n=7 (17.5%) and day 8 (n=18 (48.7%) vs n=10 (25.0%).Conclusionsdifluprednate 0.05% four times daily showed safety and efficacy profiles similar to prednisolone acetate 1% four times daily in children 0-3 years undergoing cataract surgery.


cyclophosphamide

procarbazine

doxorubicin

mitoxantrone

etoposide

Therapy-related leukemia with a novel 21q22 rearrangement. We present a case of a 59-year-old Japanese man with therapy-related acute myeloblastic leukemia (AML) after the chemotherapy for non-Hodgkin's lymphoma (NHL). Accumulated doses of cyclophosphamide , procarbazine , doxorubicin , mitoxantrone , and etoposide were 18,300 mg , 3000 mg , 580 mg , 100 mg , and 4150 mg , respectively , which had been administered for the treatment of NHL . Myeloblasts in the peripheral blood increased 43 months after the onset of NHL. He was diagnosed as having AML (M2; FAB classification). The karyotype of the bone marrow cells in the present case contained the following abnormalities: t(2;21)(q21;q22), t(8;21)(q22;q22), and add(13)(q34). In the present case, 645 base pairs of chimeric mRNA were detected by reverse transcription-polymerase chain reaction, indicating the presence of AML1/MTG8 rearrangement. Translocation (2;21)(q21;q22) has not been described previously to our knowledge. It is interesting that the breakpoint of 21q22 existed both in t(2;21) and t(8;21). The disrupted AML1 gene resulting from two 21q22 rearrangements may be involved in the pathogenesis of AML in the present case. The clinical importance of therapy-related AML having the 21q22 rearrangement remains to be examined.


rituximab

cyclophosphamide

doxorubicin

vincristine

prednisone

rituximab

Mantle cell lymphoma: therapeutic options in transplant-ineligible patients. Management of patients with newly diagnosed mantle cell lymphoma (MCL) depends on the age and fitness of the patient. For younger patients, the commonly accepted standard of care is a high-dose cytarabine-based induction chemotherapy followed by autologous stem cell transplantation (ASCT). In newly diagnosed patients with MCL ineligible for intensive therapy and ASCT , the standard-of-care has generally been R-CHOP ( rituximab , cyclophosphamide , doxorubicin , vincristine , and prednisone ) , followed by rituximab , maintenance . In recent years, bendamustine-based therapy has been increasingly adopted for older MCL patients and more recently, vincristine has been replaced by bortezomib in the R-CHOP combination as VR-CAP for previously untreated patients. Novel targeted agents now offer more promise than traditional chemotherapy or immunochemotherapy for both previously treated and untreated disease, and should also improve outcomes for older MCL patients. Here, we review standard therapies currently in use and novel agents that may soon be available for MCL patients and particularly for those unsuitable for ASCT.


panobinostat

vorinostat

Broad-Spectrum HDAC Inhibitors Promote Autophagy through FOXO Transcription Factors in Neuroblastoma. Depending on context and tumor stage, deregulation of autophagy can either suppress tumorigenesis or promote chemoresistance and tumor survival. Histone deacetylases (HDACs) can modulate autophagy; however, the exact mechanisms are not fully understood. Here , we analyze the effects of the broad-spectrum HDAC inhibitors ( HDACi ) panobinostat and vorinostat on the transcriptional regulation of autophagy with respect to autophagy transcription factor activity ( Transcription factor EB-TFEB , forkhead boxO-FOXO ) and autophagic flux in neuroblastoma cells . In combination with the late-stage autophagic flux inhibitor bafilomycin A1, HDACis increase the number of autophagic vesicles, indicating an increase in autophagic flux. Both HDACi induce nuclear translocation of the transcription factors FOXO1 and FOXO3a, but not TFEB and promote the expression of pro-autophagic FOXO1/3a target genes. Moreover, FOXO1/3a knockdown experiments impaired HDACi treatment mediated expression of autophagy related genes. Combination of panobinostat with the lysosomal inhibitor chloroquine, which blocks autophagic flux, enhances neuroblastoma cell death in culture and hampers tumor growth in vivo in a neuroblastoma zebrafish xenograft model. In conclusion, our results indicate that pan-HDACi treatment induces autophagy in neuroblastoma at a transcriptional level. Combining HDACis with autophagy modulating drugs suppresses tumor growth of high-risk neuroblastoma cells. These experimental data provide novel insights for optimization of treatment strategies in neuroblastoma.


nitrendipine

nicardipine

Nitrendipine facilitates recovery of cerebral blood flow, EEG and metabolites following cerebral ischemia in anesthetized rabbits. The effect of nitrendipine, an antihypertensive calcium antagonist, on the impairment of cerebral blood flow and EEG observed after 10-min complete cerebral ischemia in anesthetized rabbits was compared with those of nicardipine. The ischemia was produced by neck tourniquet in combination with hypotension (50-60 mmHg). Blood flow was measured by hydrogen-clearance method. Transient reactive hyperemia was observed immediately after the cessation of ischemic procedure, and was followed by a decrease in blood flow in the range of 58-73% of corresponding basal values in the total brain, cortex and thalamus. The postischemic decrease in blood flow was suppressed when nitrendipine (0.3-1 mg/kg) or nicardipine (3-10 mg/kg) was given intraduodenally before ischemia. The postischemic decrease in total intensity and frequency index in EEG recovered rapidly when nitrendipine was pretreated , whereas the recovery of EEG parameters was not obtained by the nicardipine pretreatment . These results suggest that the effect of nitrendipine and nicardipine on the postischemic cerebral blood flow may be due to the inhibition of calcium-induced contraction in cerebral vessels, whereas the discrepancy between the effects of these agents on EEG may not be due solely to the improvement in cerebral circulation. Furthermore, the improvement in postischemic cerebral energy metabolism was confirmed by nitrendipine pretreatment (0.3 mg/kg).


BU

IPSA

verapamil

carbamazepine

Effects of the serotonin-1A agonists buspirone and ipsapirone on field potentials in the hippocampus slice: comparison with carbamzepine and verapamil. The serotonin-1A agonists buspirone (BU) and ipsapirone (IPSA) have been demonstrated to exert antidepressant and anxiolytic effects. Since some antidepressant drugs and the antiepileptic substance carbamazepine have calcium antagonistic properties, the interaction of BU and IPSA with carbamazepine and the organic calcium channel blocker verapamil was analyzed in the low Mg2+ induced model epilepsy which has been shown to be suppressed specifically by organic calcium antagonists. BU and IPSA reduced the frequency of occurrence of low magnesium induced field potentials in CA1 and CA3 areas of the hippocampus slice preparation (guinea pigs) in a dose dependent manner. The subthreshold concentrations which yielded no effect were 5 mumol/l for BU and IPSA, 10 mumol/l for carbamazepine and 2 mumol/l for verapamil. Combinations of these subthreshold concentrations elicited a reduction in the repetition rate of field potentials. The results indicate that BU and IPSA behave additively with verapamil and carbamazepine , which may be due to a common action on the same subtype of calcium channels . It may be assumed that besides their action on 5-HT1A receptors BU and IPSA may also have calcium antagonistic properties.


docetaxel

trastuzumab

Safety and activity of docetaxel and trastuzumab in HER2 overexpressing metastatic breast cancer: a pilot phase II study. We conducted a pilot phase II trial of trastuzumab administered concurrently with docetaxel in women with HER2-overexpressing advanced breast cancer. Twenty-five women with HER2-positive (3+ by immunohistochemistry = 16, 2+ = 9) metastatic breast cancer received docetaxel (75 mg/m every 3 weeks for 6 cycles) and trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly thereafter). Twenty-three patients (92%) had visceral metastatic involvement. Twenty-three patients had received prior chemotherapy as part of adjuvant (18), metastatic (2), and both (3) treatment. The number of cycles administered was 121 (median 6, range 1-6). Symptomatic cardiotoxicity (GIII) occurred in one patient. The most common grade GIII/IV toxicity was neutropenia (80% of the cycles), although febrile neutropenia did not occur. No other GIII/IV toxicities were observed. Response rate was 70% (1 complete response and 15 partial responses) in 23 evaluable patients. The combination of docetaxel and trastuzumab is well tolerated and has clinically meaningful antitumor activity .


insulin-like growth factor-I

prednisolone

ursodeoxycholic acid

Choleretic actions of insulin-like growth factor-I, prednisolone, and ursodeoxycholic acid in rats. A recent study by our group demonstrated that a 1-week infusion of insulin-like growth factor-I increases bile flow volume and bile acid secretion in rats, suggesting it is important in in vivo choleresis. In the present study, the effect in rats of a single administration of insulin-like growth factor-I on bile flow volume was investigated and compared with the choleretic drugs prednisolone and ursodeoxycholic acid. A significant and long-lasting increase in bile flow volume was observed in rats treated with insulin-like growth factor-I or prednisolone. Ursodeoxycholic acid significantly, but transiently increased. Combined treatment using insulin-like growth factor-I with prednisolone or ursodeoxycholic acid additively increased bile flow volume . Overall, this study demonstrated that the stimulatory effect of insulin-like growth factor-I on bile flow volume is almost equally potent to that of prednisolone and ursodeoxycholic acid, indicating the possible therapeutic potential of insulin-like growth factor-I in cholestatic liver diseases.


oxytocin

vasopressin

The effect of anteroventral third ventricular lesions on the changes in cholecystokinin receptor density in the rat supraoptic nucleus following saline drinking. Abstract Autoradiography and computerized image analysis were used to study the density of Cholecystokinin binding sites in the supraoptic nucleus of sham-lesioned and anteroventral third ventricle (AV3V)-lesioned animals in which the magnocellular system had been activated by salt-loading with 2% saline for 48 h. Rats were maintained in metabolic cages for 5 to 7 days prior to a sham- or AV3V-lesioning procedure, and the ratio of sodium intake:urinary sodium output used as a measure of sodium excretion. Following the sham or lesion procedure half of the rats had their drinking water replaced with 2% saline and the other half were maintained on normal drinking water. Neurohypophysial hormone levels were measured by specific radioimmunoassay in trunk blood samples taken 48 h after the saline or water treatment. The AV3V-lesioned group of animals were characterized by an inability to excrete the excess sodium load and by a failure to increase secretion of both oxytocin and vasopressin into the general circulation in response to the salt-stimulus . Despite this inappropriate response, [(125) l]cholecystokinin octapeptide binding in the oxytocin-rich dorsal portion of the supraoptic nucleus was similarly elevated in both sham- and AV3V-lesioned rats following 2 days of saline treatment. These results suggest that the magnocellular oxytocin system is capable of responding to an osmotic stimulus even when the release of hormone has been severely impaired.


brinzolamide

brimonidine

Twice-daily brinzolamide/brimonidine fixed combination versus brinzolamide or brimonidine in open-angle glaucoma or ocular hypertension. To compare the intraocular pressure (IOP)-lowering efficacy and safety of brinzolamide 1% and brimonidine 0.2% fixed combination (BBFC) with that of brinzolamide 1% or brimonidine 0.2% monotherapy, all dosed 2 times per day (BID). ### design Six-month, phase 3, randomized, multicenter, double-masked clinical trial. ### participants A total of 560 patients with primary open-angle glaucoma or ocular hypertension who had insufficient IOP reduction with their current therapeutic regimen or who were receiving ≥ 2 IOP-lowering medications. ### intervention Patients received BBFC ( n = 193 ) , brinzolamide 1 % ( n = 192 ) , or brimonidine 0.2 % ( n = 175 ) BID . ### Main Outcome Measures The primary end point was mean change in diurnal IOP from baseline to month 3. Supportive end points included mean diurnal IOP change from baseline at week 2, week 6, and month 6; and mean IOP, mean IOP change from baseline, mean percentage IOP change from baseline, and percentage of patients with IOP <18 mmHg at week 2, week 6, month 3, and month 6 at each assessment time point (i.e., 9 am, 11 am, and 4 pm). Adverse events were recorded throughout the study. ### results Baseline diurnal IOP was similar among groups (mean ± standard deviation: BBFC, 25.9 ± 0.19 mmHg; brinzolamide, 25.9 ± 0.20 mmHg; brimonidine, 26.0 ± 0.19 mmHg). At month 3, BBFC lowered mean diurnal IOP from baseline to a significantly greater extent than brinzolamide (least squares [LS] mean difference: -1.4 mmHg; P < 0.0001; t test) and brimonidine (LS mean difference: -1.5 mmHg; P < 0.0001). All supportive end points corroborated the results of the primary efficacy analysis. Mean percentage reductions in IOP from baseline were 26.7% to 36.0% with BBFC, 22.4% to 27.9% with brinzolamide, and 20.6% to 31.3% with brimonidine. The most common adverse drug reactions were ocular side effects, including hyperemia, blurred vision, allergic-type reactions, and discomfort. The incidence of hyperemia of the eye was slightly lower with brinzolamide than with BBFC and brimonidine, whereas blurred vision and ocular discomfort were slightly more common with BBFC than with brinzolamide or brimonidine. ### conclusions brinzolamide 1% and brimonidine 0.2% fixed combination administered BID had a significantly greater IOP-lowering effect than either brinzolamide or brimonidine alone and displayed a safety profile consistent with its individual components.


Artemisinin

artemether

artesunate

dihydroartemisinin

artemisinin

artemisinin

Artemisinin derivatives inactivate cancer-associated fibroblasts through suppressing TGF-β signaling in breast cancer. Cancer-associated fibroblasts (CAFs) are activated fibroblasts associated with cancer. They have an important role in tumor growth and metastasis. Artemisinin ( ART ) is a sesquiterpene lactone extracted from Chinese herb qinghao , and artemether ( ARM ) , artesunate ( ARS ) and dihydroartemisinin ( DHA ) were synthesized derivatives of artemisinin , which also have anti-malarial and anti-cancer effects such as artemisinin . ### methods In this study, we investigated the in-vitro and in-vivo effects of artemisinin derivatives on inactivating cancer-associated fibroblasts and uncovered its underlying mechanism. ### results We demonstrated that ARS and DHA could revert L-929-CAFs and CAFs from activated to inactivated state in vitro. Mechanically, ARS and DHA could suppress TGF-β signaling to inhibit activation of L-929-CAFs and CAFs, and decreased interaction between tumor and tumor microenvironment. The results showed that ARS and DHA could suppress CAFs-induced breast cancer growth and metastasis in the orthotopic model. Conformably, ARS and DHA suppressed TGF-β signaling to inactivate cancer-associated fibroblasts and inhibit cancer metastasis in vivo. ### conclusions artemisinin derivatives are potential therapeutic agents for the treatment of breast cancer.


gemcitabine

trabectedin

Pharmacodynamic modeling of combined chemotherapeutic effects predicts synergistic activity of gemcitabine and trabectedin in pancreatic cancer cells . This study investigates the combined effects of gemcitabine and trabectedin (ecteinascidin 743) in two pancreatic cancer cell lines and proposes a pharmacodynamic (PD) model to quantify their pharmacological interactions. ### methods Effects of gemcitabine and trabectedin upon the pancreatic cancer cell lines MiaPaCa-2 and BxPC-3 were investigated using cell proliferation assays. Cells were exposed to a range of concentrations of the two drugs, alone and in combination. Viable cell numbers were obtained daily over 5 days. A model incorporating nonlinear cytotoxicity, transit compartments, and an interaction parameter ψ was used to quantify the effects of the individual drugs and combinations. ### results Simultaneous fitting of temporal cell growth profiles for all drug concentrations provided reasonable cytotoxicity parameter estimates (the cell killing rate constant K max and the sensitivity constant KC50) for each drug. The interaction parameter ψ was estimated as 0.806 for MiaPaCa-2 and 0.843 for BxPC-3 cells, suggesting that the two drugs exert modestly synergistic effects. ### conclusions The proposed PD model enables quantification of the temporal profiles of drug combinations over a range of concentrations with drug-specific parameters. Based upon these in vitro studies, trabectedin may have augmented benefit in combination with gemcitabine. The PD model may have general relevance for the study of other cytotoxic drug combinations.


dinaciclib

flavopiridol

regorafenib

sorafenib

Inhibition of cyclin E1 sensitizes hepatocellular carcinoma cells to regorafenib by mcl-1 suppression. To clarify the effects of cylcin E1 expression on HCC tumor progression, we studied the expression of cyclin E1 and inhibitory efficacy of regorafenib and sorafenib in HCC cells, and investigated a potential therapy that combines regorafenib treatment with cyclin E1 inhibition. ### methods Western blotting for caspase-3 and Hoechst 33225 staining was used to measure the expression level of apoptosis-related proteins under drug treatment. ### results Our results showed that enhanced expression of cyclin E1 after transfection compromised apoptosis in HCC cells induced by regorafenib or sorafenib. Conversely , down-regulation of cyclin E1 gene expression or inhibition of cyclin E1 by the cyclin-dependent kinase ( CDK ) inhibitors dinaciclib ( DIN ) or flavopiridol sensitized HCC cells to regorafenib and sorafenib by inducing apoptosis . The expression of Mcl-1, which is modulated by STAT3, plays a key role in regulating the therapeutic effects of CDK inhibitors. Xenograft experiments conducted to test the efficacy of regorafenib combined with DIN showed dramatic tumor inhibitory effects due to induction of apoptosis. Our results suggested that the level of cyclin E1 expression in HCCs may be used as a pharmacodynamic biomarker to assess the antitumor effects of regorafenib or sorafenib. ### conclusions Combining regorafenib and CDK inhibitors may enhance the clinical efficiency of the treatment of HCCs.


Levofloxacin

ambroxol

Micellar liquid chromatographic method for the simultaneous determination of Levofloxacin and Ambroxol in combined tablets: Application to biological fluids.  Levofloxacin hemihydrate ( LEV ) and ambroxol HCl ( AMB ) are available for the treatment of upper and lower respiratory tract infections . A survey of the literature reveals that two reversed phase HPLC methods were e reported for the simultaneous determination of LEV and AMB in pharmaceutical preparations. However the reported methods suffers from the low sensitivity, no application of the method in the combined tablets and no application to biological fluids. Also the toxic effects of the used solvents which are harmful to human beings. For this reason, our target was to develop a simple sensitive, less hazardous micellar HPLC method for the simultaneous determination of LEV and AMB in their combined dosage forms and plasma. ### results The method showed good linearity over the ranges of 1-44 μg/mL and 1-20 μg/mL with limits of detection 0.26 and 0.07 μg/mL and limits of quantification 0.80 and 0.20 μg/mL for LEV and AMB, respectively. The method was further extended to the determination of LEV in spiked human plasma with mean percentage recoveries of 100.10% ± 1.14 as well as determination of LEV in real human plasma without prior extraction. Statistical evaluation of the data was performed according to ICH Guidelines. ### conclusion The suggested method was successfully applied for the simultaneous analysis of the studied drugs in their co-formulated tablets and human plasma. The mean percentage recoveries in combined tablets were 100.20 ± 1.64 and 100.72 ± 1.11 for LEV and AMB, respectively and 100.10 ± 1.14 for LEV in spiked human plasma. Statistical comparison of the results with those of the comparison method revealed good agreement and proved that there were no significant difference in the accuracy and precision between the two methods respectively.


Cytarabine

etoposide

Mitoxantrone and cytarabine induction, high-dose cytarabine, and etoposide intensification for pediatric patients with relapsed or refractory acute myeloid leukemia: Children's Cancer Group Study 2951. To evaluate the response rate, survival, and toxicity of mitoxantrone and cytarabine induction, high-dose cytarabine and etoposide intensification, and further consolidation/maintenance therapies, including bone marrow transplantation, in children with relapsed, refractory, or secondary acute myeloid leukemia (AML). To evaluate response to 2-chlorodeoxyadenosine (2-CDA) and etoposide (VP-16) in patients who did not respond to mitoxantrone and cytarabine. ### Patients And Methods Patients with relapsed/refractory AML (n = 101) and secondary AML (n = 13) were entered. ### results mitoxantrone and cytarabine induction achieved a remission rate of 76% for relapsed/refractory patients and 77% for patients with secondary AML, with a 3% induction mortality rate. Cytarabine and etoposide intensification exceeded the acceptable toxic death rate of 10 % . The response rate of 2-CDA/VP-16 was 8%. Two-year overall survival was estimated at 24% and was better than historical control data. Patients with secondary AML had similar outcomes to relapsed or refractory patients. Initial remission longer than 1 year was the most important prognostic factor for patients with primary AML (2-year survival rate, 75%), whereas for patients with primary AML, with less than 12 months of initial remission, survival was 13% and was similar to that of refractory patients (6%). ### conclusion mitoxantrone and cytarabine induction is effective with reasonable toxicity in patients with relapsed/refractory or secondary AML. The cytarabine and etoposide intensification regimen should be abandoned because of toxicity. Patients with relapsed AML with initial remissions longer than 1 year have a relatively good prognosis.


warfarin

lenvatinib

Drug interactions between warfarin and lenvatinib in a patient with the CYP2C9*1/*3 and VKORC1-1639G/A genotype. lenvatinib inhibits CYP2C8. (S)-warfarin is metabolized to (S)-7-hydroxywarfarin by CYP2C9 and (S)-4'-hydroxywarfarin by CYP2C8. Here, we report drug interactions between warfarin and lenvatinib in a patient with CYP2C9*1/*3. ### Case Summary The patient was administered warfarin. His international normalized ratio (INR) was 1.92 before lenvatinib administration. On day 8 after beginning 12 mg/day lenvatinib, plasma trough concentrations of lenvatinib and (S)-warfarin were 33.3 ng/mL and 0.67 μg/mL, respectively. On day 10, his INR increased to 3.48. ### What Is New And Conclusion lenvatinib-dependent (S)-warfarin inhibition could involve CYP2C9 and CYP2C8. After initiating warfarin plus lenvatinib , INR assays are necessary .


etoposide

doxorubicin

cisplatin

melphalan

Effect of glutathione depletion on antitumor drug toxicity (apoptosis and necrosis) in U-937 human promonocytic cells. The role of intracellular oxidation.  Treatment with the DNA topoisomerase inhibitors etoposide , doxorubicin , and camptothecin , and with the alkylating agents cisplatin and melphalan , caused peroxide accumulation and apoptosis in U-937 human promonocytic cells . Preincubation with the reduced glutathione (GSH) synthesis inhibitor l-buthionine-(S,R)-sulfoximine (BSO) always potentiated peroxide accumulation. However, although GSH depletion potentiated the toxicity of cisplatin and melphalan, occasionally switching the mode of death from apoptosis to necrosis, it did not affect the toxicity of the other antitumor drugs. Hypoxia or preincubation with antioxidant agents attenuated death induction, apoptotic and necrotic, by alkylating drugs. The generation of necrosis by cisplatin could not be mimicked by addition of exogenous H(2)O(2) instead of BSO and was not adequately explained by caspase inactivation nor by a selective fall in ATP content. Treatment with cisplatin and melphalan caused a late decrease in mitochondrial transmembrane potential (DeltaPsim), which was much greater during necrosis than during apoptosis. The administration of the antioxidant agents N-acetyl-l-cysteine and butylated hydroxyanisole after pulse treatment with cisplatin or melphalan did not affect apoptosis but attenuated necrosis. Under these conditions, both antioxidants attenuated the necrosis-associated DeltaPsim decrease. These results indicate that oxidation-mediated alterations in mitochondrial function regulate the selection between apoptosis and necrosis in alkylating drug-treated human promonocytic cells.


cisplatin

carboplatin

etoposide

irinotecan

[Chemotherapy-induced myelosuppression and treatment efficacy in limited-stage disease small cell lung cancer]. We examined the association between chemotherapy-induced myelosuppression and prognosis in limited-stage disease small cell lung cancer (LD SCLC). We retrospectively analyzed 76 patients with LD SCLC who received combination cisplatin or carboplatin of etoposide or irinotecan . Patients were categorized into two groups (grade 0 to 2 or grade 3 to 4) according to the worst neutropenia, anemia, or thrombocytopenia during first-line chemotherapy and were analyzed for overall survival (OS) and time to progression (TTP). From univariate analysis, OS was significantly better in patients who developed grade 0 to 2 anemia or thrombocytopenia than those who developed grade 3 to 4. In addition, performance status, neuron-specific enolase (NSE), and pro-gastrin-releasing protein were identified as prognostic factors. By multi-variate analysis, NSE was an independent prognostic factor for OS. There were no independent prognostic factors for TTP. Myelosuppression during chemotherapy is not a prognostic factor in LD SCLC. Our results show doses of platinum doublet chemotherapy were adequate in patients with LD SCLC.


doxorubicin

etoposide

Involvement of Akt-1 and mTOR in sensitivity of breast cancer to targeted therapy. Elucidating the response of breast cancer cells to chemotherapeutic and hormonal based drugs is clearly important as these are frequently used therapeutic approaches. A signaling pathway often involved in chemo- and hormonal-resistance is the Ras/PI3K/PTEN/Akt/mTOR cascades. In the studies presented in this report, we have examined the effects of constitutive activation of Akt on the sensitivity of MCF-7 breast cancer cells to chemotherapeutic- and hormonal-based drugs as well as mTOR inhibitors. MCF-7 cells which expressed a constitutively-activated Akt-1 gene [ ∆Akt-1(CA ) ] were more resistant to doxorubicin , etoposide and 4-OH-tamoxifen ( 4HT ) than cells lacking ∆Akt-1(CA ) . Cells which expressed ∆Akt-1(CA) were hypersensitive to the mTOR inhibitor rapamycin. Furthermore, rapamycin lowered the IC50s for doxorubicin, etoposide and 4HT in the cells which expressed ∆Akt-1(CA), demonstrating a potential improved method for treating certain breast cancers which have deregulated PI3K/PTEN/Akt/mTOR signaling. Understanding how breast cancers respond to chemo- and hormonal-based therapies and the mechanisms by which they can become drug resistant may enhance our ability to treat breast cancer. These results also document the potential importance of knowledge of the mutations present in certain cancers which may permit more effective therapies.


mitomycin

doxorubicin

Mitomycin C and doxorubicin elicit conflicting signals by causing accumulation             of cyclin E prior to p21WAF1/CIP1 elevation in human hepatocellular carcinoma             cells. Proteins involved in the G1 phase of the cell cycle are aberrantly expressed,             sometimes in mutated forms, in human cancers including human hepatocellular carcinoma.             Upon attack by a DNA-damaging anticancer drug, a cell arrests at the G1 phase;             this is a safety feature prohibiting entry of DNA-damaged cells into S-phase.             p21WAF1/CIP1 prevents damaged cells from progressing to the next cell cycle. Here,             we show that , in response to mitomycin C and doxorubicin , human hepatocellular carcinoma cells generate conflicting signals , mediated by cyclin E and p21WAF1/CIP1 , which respectively accelerates and represses cell cycle transition . Exposure to             these anticancer drugs led to rapid accumulation of cyclin E in both p53-proficient             HepG2 and p53-deficient Hep3B cells. Such anticancer drug-induced cyclin E accumulation             influenced the G1-S-phase transition, but not DNA fragmentation-mediated death.             In p53-proficient HepG2 cells, accumulation of cyclin E was followed by an increase             in the level of p53-dependent p21WAF1/CIP1, thereby inhibiting further the G1-S-phase             transition. Sublethal drug concentrations also induced rapid accumulation of cyclin             E, but p21WAF1/CIP1 accumulation was delayed, further facilitating the G1-S-phase             transition. Eventually, most cells arrested in G2/M. Thus, mitomycin C- or doxorubicin-induced             conflicting signals, mediated by cyclin E and p21WAF1/CIP1, are in play in human             hepatocellular carcinoma cells. Damaged G1 cells either immediately enter S-phase,             or do not do so at all, depending on the extent of DNA damage.


topotecan

irinotecan

Topoisomerase I inhibitors combination chemotherapy in non-small cell lung cancer.  In the last years , the main topoisomerase I inhibitors ( TP1-I ) ( i.e. topotecan and irinotecan ) have been used in combination chemotherapy in non-small cell lung cancer . Several drugs (also alternative to cisplatin) have been used in combination with TP1-I, but to date the higher remission rate obtained with combinations is not translated into a more prolonged survival in comparison with TP1-I given alone. On the other hand, the toxicity of TP1-I combinations is greater than those of TP1-I used alone. The superior efficacy of combinations versus TP1-I used alone remains an open question. Furthermore, the best schedule for TP1-I has not been completely elucidated. Randomised studies are few (only two phase III trials) and only controlled studies will be able to clarify the best TP1-I combination regimen.


inosine

interferon alfa

ribavirin

Merimepodib

Merimepodib, pegylated interferon, and ribavirin in genotype 1 chronic hepatitis C pegylated interferon and ribavirin nonresponders.  Merimepodib ( MMPD ) is an orally administered , inosine monophosphate dehydrogenase inhibitor that has shown antiviral activity in nonresponders with chronic hepatitis C ( CHC ) when combined with pegylated interferon alfa 2a ( Peg-IFN-alfa-2a ) and ribavirin ( RBV ) . We conducted a randomized, double-blind, multicenter, phase 2b study to evaluate the antiviral activity, safety, and tolerability of MMPD in combination with Peg-IFN-alfa-2a and RBV in patients with genotype 1 CHC who were nonresponders to prior therapy with Peg-IFN and RBV. Patients received 50 mg MMPD, 100 mg MMPD, or placebo every 12 hours, in addition to Peg-IFN-alfa-2a and RBV, for 24 weeks. Patients with a 2-log or more decrease from baseline or undetectable hepatitis C virus (HCV) RNA levels at week 24 were then eligible to continue Peg-IFN-alfa-2a and RBV for a further 24 weeks, followed by 24 weeks of follow-up. The primary efficacy endpoint was sustained virological response (SVR) rate at week 72 in all randomized patients who received at least one dose of study drug and had a history of nonresponse to standard therapy. A total of 354 patients were randomized to treatment (117 to placebo; 119 to 50 mg MMPD; 118 to 100 mg MMPD), and 286 completed the core study. The proportion of patients who achieved SVR was similar among the treatment groups: 6% (6/107) for 50 mg MMPD, 4% (5/112) for 100 mg MMPD, and 5% (5/104) for placebo (P = 0.8431). Adverse-event profiles for the MMPD combination groups were similar to that for Peg-IFN-alfa and RBV alone. Nausea, arthralgia, cough, dyspnea, neutropenia, and anemia were more common in patients taking MMPD. ### conclusion The addition of MMPD to Peg-IFN-alfa-2a and RBV combination therapy did not increase the proportion of nonresponder patients with genotype 1 CHC achieving an SVR.


carbenicillin

gentamicin

The use of antibiotics in the culture of non-sterile plant protoplasts. The use of antibiotics to control infections in cultures of protoplasts of leaf mesophyll cells has been examined. The antifungal agents nystatin and amphotericin B were non-toxic to protoplasts at concentrations that controlled fungal growth (25 units and 2.5 μg/ml respectively). Of the antibacterial agents examined , only carbenicillin and , to a lesser extent , gentamicin were active against the bacteria usually encountered whilst still permitting normal protoplast metabolism and regeneration . The most satisfactory control of contaminating microorganisms was obtained with a combination of nystatin (25 units/ml) or amphotericin B (2.5 μg/ml) and carbenicillin (250 μg/ml).


cisplatin

gemcitabine

etoposide

doxorubicin

paclitaxel

The anti-tumor activity of E1A and its implications in cancer therapy. The adenovirus type 5 E1A protein (E1A) plays a critical role in anti-cancer gene therapy and has been tested in clinical trials. The expression of E1A significantly reduces tumorigenesis, promotes cell death, and inhibits cancer cell mobility. Chemosensitization is one of the anti-tumor effects of E1A , increasing in vitro and in vivo sensitization of anti-cancer drugs , including cisplatin , gemcitabine , etoposide , doxorubicin , paclitaxel , and tumor necrosis factor-related apoptosis-inducing ligand and histone deacetylase inhibitors in different types of cancer cells . E1A also demonstrates anti-metastasis activity through various molecular mechanisms such as the repression of protease expression, suppression of HER2/neu and downregulation of microRNA (miR-520h). Moreover, E1A has been reported to reprogram transcription in tumor cells and stabilize tumor suppressors such as PP2A/C, p21 and p53. Because E1A plays a potentially significant role in anti-tumor therapy, there exists an urgent need to study the anti-cancer activities of E1A. This paper presents a review of our current understanding of the tumor-suppressive functions and molecular regulation of E1A, as well as the potential clinical applications of E1A.


etoposide

doxorubicin

pirarubicin

Drug sensitivity and drug resistance profiles of human intrahepatic cholangiocarcinoma cell lines. To study the effect of a number of chemotherapeutic drugs on five human intrahepatic cholangiocarcinoma (CCA) cell lines. The expressions of genes that have been proposed to influence the resistance of chemotherapeutic drugs including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), glutathione-S-transferase P1 (GSTP1), multidrug resistance protein (MDR1) and multidrug resistance-associated proteins (MRPs) were also determined. ### methods Five human CCA cell lines (KKU-100, KKU-M055, KKU-M156, KKU-M214 and KKU-OCA17) were treated with various chemotherapeutic drugs and growth inhibition was determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Semi-quantitative levels of gene expression were determined by a reverse transcriptase polymerase chain reaction (RT-PCR). Results of IC(50) values and the ratios of gene expression were analyzed by linear regression to predict their relationship. ### results Among five CCA cell lines, KKU-M055 was the most sensitive cell line towards all chemotherapeutic drugs investigated, particularly taxane derivatives with IC(50) values of 0.02-3 nmol/L, whereas KKU-100 was apparently the least sensitive cell line. When compared to other chemotherapeutic agents, doxorubicin and pirarubicin showed the lowest IC(50) values (<5 mumol/L) in all five CCA cell lines. Results from RT-PCR showed that TS, MRP1, MRP3 and GSTP1 were highly expressed in these five CCA cell lines while DPD and MRP2 were only moderately expressed. It should be noted that MDR1 expression was detected only in KKU-OCA17 cell lines. A strong correlation was only found between the level of MRP3 expression and the IC(50 ) values of etoposide , doxorubicin and pirarubicin ( r = 0.86 - 0.98 , P<0.05 ) . ### conclusion Sensitivity to chemotherapeutic agents is not associated with the histological type of CCA. Choosing of the appropriate chemotherapeutic regimen for the treatment of CCA requires knowledge of drug sensitivity. MRP3 was correlated with resistance of CCA cell lines to etoposide, doxorubicin and pirarubicin, whereas other chemotherapeutic drugs showed no association. The role of this multidrug resistance-associated protein, MRP3, in chemotherapeutic resistance in CCA patients needs to be further investigated.


doxorubicin

daunorubicin

vincristine

etoposide

Multiple drug-resistant C6 glioma cells cross-resistant to irradiation. Although many advances in antineoplastic therapy have taken place, a clinical breakthrough in the therapy of malignant gliomas is still required. One of the reasons for this is the poor response to cytotoxic drugs and irradiation. We established a subline of the rat glioma cell line C6, named C6,5 x 10(-7) Dox, by exposure to increasing doses of doxorubicin for 5 months. C6,5 x 10(-7) Dox cells expressed high levels of P-glycoprotein (Pgp), known to function as an energy-dependent efflux pump for lipophilic drugs causing the multidrug resistance phenotype. Pgp, which normally has a molecular weight of 170 to 180 kd, appears in C6,5 x 10(-7) Dox cells as two bands with a molecular weight of 140 and 120 kd in western blots. In addition to the typical cross-resistance to doxorubicin , daunorubicin , vincristine and etoposide , we observed a significant resistance of the C6,5 x 10(-7 ) Dox cell line to irradiation , which can not be explained by Pgp-expression .


endostatin

doxycycline

[ Effects of endostatin and doxycycline on microcirculation patterns in melanoma and their relevant molecular mechanisms ] . To investigate the effects of endostatin and doxycycline on microcirculation patterns in melanoma and their molecular mechanisms. ### methods To establish mouse B16 melanoma model by subcutaneous injection of B16 melanoma cell suspension. The mice were divided into 3 experimental groups and 1 control group. To treat the mice in the 3 experimental groups with endostatin, doxycycline, endostatin and doxycycline, respectively, and the control group without any treatment. The tumor volume was measured and recorded to make comparison of their growth rate. To assess the expression of MMP-2, MMP-9 and TIMP-2 by immunohistochemical staining. The three microcirculation patterns of endothelium-dependent vessels, mosaic vessels and vasculogenic mimicry were counted. The activity of MMP-2, MMP-9 between different groups was examined by gelatin zymography. ### results Tumor growth in the three experimental groups was statistically significantly slower than that in the control group. The expression of MMP-2, MMP-9 and TIMP-2 in each treated group was significantly different with that in the control group. The amount of three microcirculation patterns in three experimental groups was less than that of the control group, and the amount of MV and VM in each experimental group was significantly less than that in the control group. By gelatin zymography, the enzyme activity of MMP-9, actived-MMP-2 and MMP-2/proMMP-2 in ES, DOX and ES + DOX group was lower than that in the control group, but the enzyme activity of pro-MMP-2 among the four groups was not significantly different. ### conclusion The combined use of doxycycline and endostatin in melanoma can inhibit the expression of MMPs, influencing the formation of different microcirculation patterns in melanoma.


rapamycin

everolimus

temsirolimus

FLT3 inhibitors for the treatment of acute myeloid leukemia. The fms-like receptor tyrosine kinase-3 (FLT3), which is important for the normal development of hematopoietic stem cells and cells of the immune system, is frequently mutated in patients with acute myeloid leukemia (AML). FLT3 is, therefore, a potential therapeutic target in AML. Recently, FLT3 inhibitors have shown therapeutic activity in AML patients with FLT3 mutations. sorafenib and sunitinib were the first FLT3 inhibitors to be studied in the clinic and have the most clinically relevant data. Limited data are available for midostaurin (PKC412), lestaurtinib (CEP-701), tandutinib (MLN518), AC220, and KW-2449. It is likely that optimal application of these agents will involve combinations of inhibitors and combinations of inhibitors and chemotherapy , potentially with a mammalian target of rapamycin inhibitor such as everolimus or temsirolimus . This review discusses the theoretical rationale for the use of these agents and summarizes the relevant clinical data.


etoposide

doxorubicin

cisplatin

mitotane

Targeting heterogeneity of adrenocortical carcinoma: Evaluation and extension of preclinical tumor models to improve clinical translation. In recent years it has been recognized that clinical translation of novel therapeutic strategies for patients with adrenocortical carcinoma (ACC) often fails. These disappointing results indicate that the currently utilized tumor models only poorly reflect relevant pathophysiology and, thereby, do not predict clinical applicability of novel pharmacological approaches. However, also the development of new preclinical ACC models has remained a challenge with only one human cell line (NCI-H295R) and one recently established human pediatric xenograft model (SJ-ACC3) being available for this highly heterogeneous malignancy. Our current study furthermore reveals a poor reproducibility of therapeutic action between different clones of the most commonly used tumor model NCI-H295R. In an attempt to broaden the current preclinical armamentarium, we aimed at the development of patient-individual tumor models. During these studies, one xenograft (MUC-1) displayed marked engraftment and sustained tumor growth. MUC-1 tumor analysis revealed highly vascularized, proliferating and SF-1 positive xenografts. In a next step, we characterized all currently available human tumor models for ACC for Ki67, SF-1 and EGF-receptor status in comparison with MUC-1-xenografts. In addition, we established a primary culture, which is now viable over 31 passages with sustained nuclear SF-1 and cytoplasmic 3βHSD immuno-positivity. Subsequent investigation of therapeutic responsiveness upon treatment with the current systemic gold standard EDP-M ( etoposide , doxorubicin , cisplatin and mitotane ) demonstrated maintenance of the clinically observed drug resistance for MUC-1 exclusively . In summary, we provide evidence for a novel patient-derived tumor model with the potential to improve clinical prediction of novel therapeutic strategies for patients with ACC.


Oxaliplatin

gemcitabine

Gemcitabine and oxaliplatin: a safe and active regimen in poor prognosis advanced non-small cell lung cancer patients. Most patients with non-small cell lung cancer (NSCLC) cannot tolerate a cisplatin-based chemotherapy because of old age, general conditions, and/or multiorgan metastatic sites. Oxaliplatin is active in NSCLC , offers advantage in terms of toxicity , and shows synergism with gemcitabine . The aims of this phase II study were to evaluate the response rate and toxicity of the gemcitabine-oxaliplatin combination in patients with advanced NSCLC and poor prognosis. ### methods Patients were given a gemcitabine infusion (1000 mg/m(2) over 30 min on days 1 and 8) followed by oxaliplatin (65 mg/m(2) over 120 min on days 1 and 8) every 21 days for six cycles. ### results Thirty-two patients with poor-prognosis advanced NSCLC received 136 cycles. There were 25 males and seven females, and the median age was 65 years (range 29-76). Fifty-six percent of patients had adenocarcinoma, and 31% had squamous cell carcinoma. Sixty-six percent of patients had stage IV disease, and 34% had stage IIIB disease. Eastern cooperative oncology group (ECOG) performance status was 2-3 in 50%, 1 in 44%, and 0 in 6% of patients. Eight patients (25%) had been previously treated with cisplatin or carboplatin. All patients were symptomatic. Of the 32 patients who received study drug, five (16%) achieved partial response, six (19%) had minor response, three (9%) had stable disease, and 15 (47%) progressed. The median overall survival was 27 weeks. Thirty-one patients were evaluable for toxicity: seven patients (23%) had grade 3-4 thrombocytopenia with no bleeding; four patients (13%) had grade 3-4 neutropenia with no febrile neutropenia, and three patients (10%) had grade 3 anemia. Two patients (6%) had grade 3, and six patients (19%) had grade 1-2 neurotoxicity. ### conclusion The combination of gemcitabine and oxaliplatin seems to be well tolerated and active in patients with poor prognosis advanced NSCLC and deserves further evaluation in phase II clinical trials.


docetaxel

abiraterone

enzalutamide

cabozantinib

carboplatin

cabazitaxel

Role of free testosterone levels in patients with metastatic castration-resistant prostate cancer receiving second-line therapy. A range of new treatment options has recently become available for patients with advanced metastatic castration-resistant prostate cancer (mCRPC). Androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone is continued when performing chemotherapy or androgen deprivation with new second-generation therapeutic agents such as enzalutamide or abiraterone acetate. Despite the fact that free testosterone (FT) is the biologically active form, it is common practice that androgen suppression is monitored via total testosterone levels only. The aim of the present study was to evaluate the role of FT as a prognostic biomarker for cancer-specific survival (CSS) and its feasibility as an ADT monitoring biomarker in patients with mCRPC for the first time. The requirement for continued ADT in mCRPC patients is discussed within the basis of the current literature. A total of 34 patients with continuous measurements of FT levels and mCRPC status underwent therapy with docetaxel , abiraterone acetate , enzalutamide , cabozantinib , carboplatin or cabazitaxel . Data were obtained from the Departments of Urology and Urological Oncology, Hannover Medical School (Hannover, Germany) between March 2009 and April 2014. A cutoff point of 0.5 pg/ml was used to discriminate between patients according to FT levels. Statistical evaluation of CSS was performed by applying Kaplan Meier survival estimates, multivariate Cox regression analyses and log-rank tests. The median age of all 34 patients was 72 years (range, 51-86 years). The mean follow-up interval was 16.1 months (range, 0.7-55.6 months). Despite the fact that all patients were undergoing androgen deprivation, the mean serum FT levels for each patient varied; the mean FT concentration in the cohort was 0.328 pg/ml, ranging from 0.01-9.1 pg/ml. A notable difference with regard to CSS was observed for patients with regard to serum FT concentration; CSS was significantly longer for patients with a serum FT level below the cutoff level (43.6 vs. 17.3 months, respectively, P=0.0063). Upon multivariate Cox regression analysis, the mean FT concentration during treatment remained a significant prognostic factor for CSS (hazard ratio, 1.22; 95% confidence interval, 1.03-1.43; P=0.0182). In conclusion, in patients with mCRPC, the serum FT level is a strong predictor of CSS in patients under therapy with second-line anti-hormonal therapeutic medication and chemotherapy. It may be concluded that FT levels should be included into the routine control of androgen suppression while under treatment with ADT and second-generation hormonal therapy.


bismuth

sucralfate

Pharmacological interventions for prevention and treatment of upper gastrointestinal bleeding in newborn infants. Upper gastrointestinal bleeding is typically a mild, self-limiting condition that can affect both preterm and term neonates, although it can be severe particularly when associated with co-morbidities. Pharmacological interventions with a proton pump inhibitor ( PPI ) , H2 receptor antagonist ( H2RA ) , antacid , bismuth and sucralfate may have effects on both the prevention and treatment of upper gastrointestinal bleeding in infants . ### objectives To assess how different pharmacological interventions (PPIs, H2RAs, antacids, sucralfate or bismuth salts) administered to preterm and term neonates for the prevention or treatment of upper gastrointestinal bleeding to reduce morbidity and mortality compare with placebo or no treatment, supportive care, or each other. ### Search Methods We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 6), MEDLINE via PubMed (1966 to 12 July 2018), Embase (1980 to 12 July 2018), and CINAHL (1982 to 12 July 2018). We also searched clinical trial databases, conference proceedings, the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials, and online for Chinese literature articles. ### Selection Criteria We selected randomised, quasi-randomised and cluster-randomised trials involving preterm and term neonates. Trials were included if they used a proton pump inhibitor, H2 receptor antagonist, antacid, sucralfate or bismuth either for the prevention or treatment of upper gastrointestinal bleeding. ### Data Collection And Analysis Two review authors independently assessed the eligibility of studies for inclusion, extracted data and assessed methodological quality. We conducted meta-analysis using a fixed-effect model. We used the GRADE approach to assess quality of evidence. ### Main Results Eleven studies with 818 infants met the criteria for inclusion in this review.Four trials with 329 infants assessed the use of an H2 receptor antagonist for prevention of upper gastrointestinal bleeding in high-risk newborn infants. Meta-analysis of these four trials identified a reduction in any upper gastrointestinal bleeding when using an H2 receptor antagonist (typical risk ratio (RR) 0.36, 95% confidence interval (CI) 0.22 to 0.58; typical risk difference (RD) -0.20, 95% CI -0.28 to -0.11; number needed to treat for an additional beneficial outcome (NNTB) 5, 95% CI 4 to 9). The quality of evidence was moderate. A single trial with 53 infants assessing prevention of upper gastrointestinal bleeding reported no difference in mortality in infants assigned H2 receptor antagonist versus no treatment; however the quality of evidence was very low.Seven trials with 489 infants assessed an inhibitor of gastric acid (H2 receptor antagonist or proton pump inhibitor) for treatment of gastrointestinal bleeding in newborn infants. Meta-analysis of two trials (131 infants) showed no difference in mortality from use of a H2 receptor antagonist compared to no treatment. The quality of evidence was low. Meta-analysis of two trials (104 infants) showed a reduction in duration of upper gastrointestinal bleeding from use of an inhibitor of gastric acid compared to no treatment (mean difference -1.06 days, 95% CI -1.28 to -0.84). The quality of evidence was very low. Meta-analysis of six trials (451 infants) showed a reduction in continued upper gastrointestinal bleeding from use of any inhibitor of gastric acid compared to no treatment (typical RR 0.36, 95% CI 0.26 to 0.49; typical RD -0.26, 95% CI -0.33, -0.19; NNTB 4, 95% CI 3 to 5). The quality of evidence was low. There were no significant subgroup differences in duration of upper gastrointestinal bleeding or of continued upper gastrointestinal bleeding according to type of inhibitor of gastric acid. A single trial (38 infants) reported no difference in anaemia requiring blood transfusion from use of a H2 receptor antagonist compared to no treatment.Although no serious adverse events were reported from the use of a H2 receptor antagonist or proton pump inhibitor, some neonatal morbidities - including necrotising enterocolitis, ventilator-associated pneumonia, duration of ventilation and respiratory support, and duration of hospital stay - were not reported. Long-term outcome was not reported. ### Authors Conclusions There is moderate-quality evidence that use of an H2 receptor antagonist reduces the risk of gastrointestinal bleeding in newborn infants at high risk of gastrointestinal bleeding. There is low-quality evidence that use of an inhibitor of gastric acid (H2 receptor antagonist or proton pump inhibitor) reduces the duration of upper gastrointestinal bleeding and the incidence of continued gastric bleeding in newborn infants with gastrointestinal bleeding. However, there is no evidence that use of an inhibitor of gastric acid in newborn infants affects mortality or the need for blood transfusion. As no study reported the incidence of necrotising enterocolitis, ventilator- or hospital-associated pneumonia, sepsis, or long-term outcome, the safety of inhibitors of gastric acid secretion is unclear.


Doxorubicin

lapatinib

Doxorubicin and lapatinib combination nanomedicine for treating resistant breast cancer . Our objective was to design a polymeric micelle-based doxorubicin and lapatinib combination therapy for treating multidrug resistant (MDR) breast cancers. Poly(ethylene glycol)-block-poly(2-methyl-2-benzoxycarbonylpropylene carbonate) (PEG-PBC) polymers were synthesized for preparing doxorubicin and lapatinib loaded micelles using a film dispersion method. Micelles were characterized by determining critical micelle concentration (CMC), particle size distribution, and drug loading. The anticancer effects were determined in vitro with MTT assays as well as with lactate dehydrogenase (LDH) release studies. In addition, the cellular uptake of drug-loaded micelles was determined with fluorescence microscopy and flow cytometry. Finally, in vivo anticancer activity and tolerance of developed formulations were evaluated in resistant breast tumor bearing mice. PEG5K-PBC7K polymer synthesized in this study had a low CMC value (1.5 mg/L) indicating an excellent dynamic stability. PEG-PBC micelles could efficiently load both doxorubicin and lapatinib drugs with a loading density of 21% and 8.4%, respectively. The mean particle size of these micelles was 100 nm and was not affected by drug loading. The use of lapatinib as an adjuvant sensitized drug resistant MCF-7/ADR cells to doxorubicin treatment. Cellular uptake studies showed enhanced doxorubicin accumulation in MCF-7/ADR cells in the presence of lapatinib. The doxorubicin and lapatinib combination therapy showed a significant decrease in tumor growth compared to doxorubicin monotherapy. In conclusion, we have developed PEG-PBC micelle formulations for the delivery of doxorubicin and lapatinib. The combination therapy of doxorubicin plus lapatinib has a great potential for treating MDR breast cancer.


ritonavir

docetaxel

Ritonavir inhibits intratumoral docetaxel metabolism and enhances docetaxel antitumor activity in an immunocompetent mouse breast cancer model. docetaxel (Taxotere(®)) is currently used intravenously as an anticancer agent and is primarily metabolized by Cytochrome P450 3A (CYP3A). The HIV protease inhibitor ritonavir , a strong CYP3A4 inhibitor , decreased first-pass metabolism of orally administered docetaxel . Anticancer effects of ritonavir itself have also been described. We here aimed to test whether ritonavir co-administration could decrease intratumoral metabolism of intravenously administered docetaxel and thus increase the antitumor activity of docetaxel in an orthotopic, immunocompetent mouse model for breast cancer. Spontaneously arising K14cre;Brca1(F/F) ;p53(F/F) mouse mammary tumors were orthotopically implanted in syngeneic mice lacking Cyp3a (Cyp3a(-/-)) to limit ritonavir effects on systemic docetaxel clearance. Over 3 weeks, docetaxel (20 mg/kg) was administered intravenously once weekly, with or without ritonavir (12.5 mg/kg) administered orally for 5 days per week. Untreated mice were used as control for tumor growth. ritonavir treatment alone did not significantly affect the median time of survival (14 vs. 10 days). Median time of survival in docetaxel-treated mice was 54 days. ritonavir co-treatment significantly increased this to 66 days, and substantially reduced relative average tumor size, without altering tumor histology. Concentrations of the major docetaxel metabolite M2 in tumor tissue were reduced by ritonavir co-administration, whereas tumor RNA expression of Cyp3a was unaltered. In this breast cancer model, we observed no direct antitumor effect of ritonavir alone, but we found enhanced efficacy of docetaxel treatment when combined with ritonavir. Our data, therefore, suggest that decreased docetaxel metabolism inside the tumor as a result of Cyp3a inhibition contributes to increased antitumor activity.