Cancer chemotherapy and pharmacology
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Cancer Chemother. Pharmacol. · May 2015
Dose selection of siltuximab for multicentric Castleman's disease.
Siltuximab is a monoclonal antibody that binds to interleukin (IL)-6 with high affinity and specificity; C-reactive protein (CRP) is an acute-phase protein induced by IL-6. CRP suppression is an indirect measurement of IL-6 activity. Here, modeling and simulation of the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between siltuximab and CRP were used to support dose selection for multicentric Castleman's disease (CD). ⋯ PK/PD modeling was used to select doses for further development of siltuximab in multicentric CD. The dosing recommendation was also supported by the observed efficacy dose-response relationship. CRP suppression in the subsequent randomized multicentric CD study was in agreement with the modeling predictions.
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Cancer Chemother. Pharmacol. · May 2015
Levels of sirolimus in saliva and blood following oral topical sustained-release varnish delivery system application.
Sirolimus (rapamycin) is a mammalian target of rapamycin pathway blocker. The efficacy of sirolimus is currently studied for its antiproliferative properties in various malignancies and particularly in squamous cell carcinoma and other oral disorders. Topical application at the oral cavity can augment sirolimus availability at the site of action by increasing sirolimus levels in saliva and hence efficacy, along with improved safety (low levels in the blood to avoid side effects) and compliance. Our purpose was to evaluate the release profile and safety of a topical sirolimus sustained-release varnish drug delivery system. ⋯ After an application of sirolimus sustained-release varnish drug delivery system, prolonged drug levels can be achieved in the saliva. The oral topical sirolimus concentrations were potentially therapeutic along with minimal systemic exposure. These results broaden the potential clinical use of sustained-release oral topical rapalogs.
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Cancer Chemother. Pharmacol. · Mar 2015
Randomized Controlled Trial Comparative StudyA randomized phase II study of combination therapy with S-1, oral leucovorin, and oxaliplatin (SOL) and mFOLFOX6 in patients with previously untreated metastatic colorectal cancer.
Biochemical modulation of 5-fluorouracil (5-FU) by leucovorin (LV) enhances antitumor activity. LV is thus often added to 5-FU-based regimens for the treatment of metastatic colorectal cancer (mCRC). A combination of S-1, oxaliplatin, and LV (SOL) was shown to be feasible, effective, and safe in a previous phase I trial. We therefore conducted a randomized phase II trial to evaluate efficacy and safety of SOL compared with mFOLFOX6. ⋯ SOL demonstrated promising efficacy and acceptable toxicity as first-line chemotherapy for mCRC. Further studies of SOL combined with molecular target agents are warranted.
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Cancer Chemother. Pharmacol. · Mar 2015
Safety and activity of temsirolimus and bevacizumab in patients with advanced renal cell carcinoma previously treated with tyrosine kinase inhibitors: a phase 2 consortium study.
Bevacizumab or temsirolimus regimens have clinical activity in the first-line treatment of advanced renal cell carcinoma (RCC). This phase I/II trial was conducted to determine the safety of combining both agents and its efficacy in RCC patients who progressed on at least one prior anti-VEGF receptor tyrosine kinase inhibitor (RTKI) agent. ⋯ Temsirolimus and bevacizumab is a feasible combination in patients with advanced RCC previously exposed to oral anti-VEGF agents. The safety and efficacy results warrant further confirmatory studies in this patient population.
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Cancer Chemother. Pharmacol. · Feb 2015
Intravenous 3-weekly paclitaxel and metronomic oral cyclophosphamide in patients with advanced urothelial cancer previously treated with gemcitabine and platinum.
Taxane-based chemotherapy is one of the most commonly used agents in patients with advanced urothelial carcinoma who developed disease progression after gemcitabine and cisplatin combination chemotherapy. The response rates, however, are dismal reported around 10-20%. Recently, promising efficacy results of paclitaxel when combined with oral cyclophosphamide as metronomic therapy have been reported. ⋯ Metronomic oral cyclophosphamide combined with paclitaxel appears to be both efficacious and safe as a salvage chemotherapy, particularly in heavily pretreated patients with advanced urothelial carcinoma after gemcitabine-cisplatin failure.