Journal ArticleDOI
A phase I clinical, plasma, and cellular pharmacology study of gemcitabine.
James L. Abbruzzese,R Grunewald,E A Weeks,D Gravel,T Adams,B Nowak,Shin Mineishi,P Tarassoff,W Satterlee,Martin N. Raber +9 more
TLDR
The recommended dose for phase II clinical trials in solid tumors is 790 mg/m2/wk, and the dose-limiting toxicity was myelosuppression, with thrombocytopenia and anemia quantitatively more important than granulocy topenia.Abstract:
A novel deoxycytidine analog, gemcitabine (2',2'-difluorodeoxycytidine [dFdC]), has been studied in a phase I clinical and pharmacology trial. Doses ranging from 10 to 1,000 mg/m2 were administered over 30 minutes weekly times 3 weeks every 4 weeks. The maximum-tolerated dose (MTD) was 790 mg/m2. The dose-limiting toxicity was myelosuppression, with thrombocytopenia and anemia quantitatively more important than granulocytopenia. Nonhematologic toxicity was minimal. Two responses in patients with adenocarcinomas of the colon and lung were documented. The maximum dFdC plasma concentration, reached after 15 minutes of infusion, was proportional to the total dose administered. Elimination, due mainly to deamination, was rapid (terminal half-life [t1/2], 8.0 minutes) and dose independent. The deamination product 2',2'-difluorodeoxyuridine (dFdU) was eliminated with biphasic kinetics characterized by a long terminal phase (t1/2, 14 hours); it was the sole metabolite detected in urine. The concentration of dFdC 5'-triphosphate in circulating mononuclear cells increased in proportion to the dFdC dose at infusions between 35 and 250 mg/m2. No further increment in dFdC 5'-triphosphate (dFdCTP) was observed at higher doses, which resulted in plasma dFdC concentrations greater than 20 mumol/L (350 to 1,000 mg/m2), suggesting saturation of dFdC 5'-phosphate accumulation. The recommended dose for phase II clinical trials in solid tumors is 790 mg/m2/wk.read more
Citations
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Journal ArticleDOI
Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer
Kenneth P. Olive,Michael A. Jacobetz,Christian Davidson,Aarthi Gopinathan,Aarthi Gopinathan,Dominick J.O. McIntyre,Davina J. Honess,Basetti Madhu,Mae A. Goldgraben,Meredith E. Caldwell,David Allard,Kristopher K. Frese,Gina M. DeNicola,Gina M. DeNicola,Christine Feig,Chelsea Combs,Stephen P. Winter,Heather Ireland-Zecchini,Stefanie Reichelt,William J. Howat,Alex R. Chang,Mousumi Dhara,Lifu Wang,Lifu Wang,Felix Rückert,Robert Grützmann,Christian Pilarsky,Kamel Izeradjene,Sunil R. Hingorani,Pearl S. Huang,Susan E. Davies,William Plunkett,Merrill J. Egorin,Ralph H. Hruban,Nigel Whitebread,Karen McGovern,Julian Adams,Christine A. Iacobuzio-Donahue,John R. Griffiths,David A. Tuveson +39 more
TL;DR: Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, it is found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA.
Journal Article
Action of 2',2'-difluorodeoxycytidine on DNA synthesis.
TL;DR: Qualitative and quantitative differences in the molecular actions of dFdC and arabinosylcytosine on DNA metabolism are demonstrated, but are consistent with an important role for such incorporation in the toxicity of d FdC.
Book ChapterDOI
Overview of Resistance to Systemic Therapy in Patients with Breast Cancer
TL;DR: The rates of local and systemic recurrence vary within different series, but in general, distant recurrences are dominant, strengthening the hypothesis that breast cancer is a systemic disease from presentation.
Journal ArticleDOI
Dose Escalation Methods in Phase I Cancer Clinical Trials
TL;DR: Dose escalation methods for phase I trials are reviewed, including the rule-based and model-based dose escalation methods that have been developed to evaluate new anticancer agents and specific methods for drug combinations as well as methods that use a time-to-event endpoint or both toxicity and efficacy as endpoints.
Journal ArticleDOI
Cellular pharmacology of gemcitabine
TL;DR: Evidence that up- or down-regulation of the multiple membrane transporters, target enzymes, enzymes involved in the metabolism of gemcitabine and alterations in the apoptotic pathways may confer sensitivity/resistance to this drug has been provided in experimental models and more recently in the clinical setting.
References
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Journal Article
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