کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2123827 1547202 2010 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی تحقیقات سرطان
پیش نمایش صفحه اول مقاله
Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies
چکیده انگلیسی

AimPhase I study of seliciclib (CYC202, R-roscovitine), an inhibitor of cyclin-dependent kinases 2, 7 and 9, causing cell cycle changes and apoptosis in cancer cells.Patients and methodsThis phase I trial aimed at defining the toxicity profile, the maximum tolerated dose (MTD), the recommended phase II dose (RD) and the main pharmacokinetic and pharmacodynamic parameters of oral seliciclib. Three schedules were evaluated: seliciclib given twice daily for 5 consecutive days every 3 weeks (schedule A), for 10 consecutive days followed by 2 weeks off (schedule B) and for 3 d every 2 weeks (schedule C).ResultsFifty-six patients received a total of 218 cycles of seliciclib. Dose-Limiting Toxicities (DLT) consisting of nausea, vomiting, asthenia and hypokalaemia occurred at 1600 mg bid for schedule A and in schedule C, DLT of hypokalaemia and asthenia occurred at 1800 mg bid. The evaluation of longer treatment duration in schedule B was discontinued because of unacceptable toxicity at lower doses. Other adverse events included transient serum creatinine increases and liver dysfunctions. Pharmacokinetic data showed that exposure to seliciclib and its carboxylate metabolite increased with increasing dose. Soluble cytokeratin 18 fragments allowed monitoring of seliciclib-induced cell death in the blood of patients treated with seliciclib at doses above 800 mg/d. One partial response in a patient with hepatocellular carcinoma and sustained tumour stabilisations were observed.ConclusionsThe MTD and RD for seliciclib are 1250 mg bid for 5 d every 3 weeks and 1600 mg bid for 3 d every 2 weeks, respectively.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Cancer - Volume 46, Issue 18, December 2010, Pages 3243–3250
نویسندگان
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