Modulation of cell cycle progression in human tumors: a pharmacokinetic and tumor molecular pharmacodynamic study of cisplatin plus the Chk1 inhibitor UCN-01 …

RP Perez, LD Lewis, AP Beelen, AJ Olszanski… - Clinical cancer …, 2006 - AACR
RP Perez, LD Lewis, AP Beelen, AJ Olszanski, N Johnston, CH Rhodes, B Beaulieu…
Clinical cancer research, 2006AACR
Abstract Background: UCN-01, a Chk1 inhibitor, abrogates S and G2 arrest and enhances
cancer cell killing by DNA-damaging drugs in preclinical models. UCN-01 avidly binds α1-
acid glycoprotein in plasma; whether sufficient drug concentrations are achieved in human
tumors is unknown. A phase I trial tested the hypothesis that UCN-01 abrogates cisplatin-
induced cell cycle arrest (in tumors) at tolerable doses. Methods: Patients with advanced
cancer received iv cisplatin, followed 22 hours later by UCN-01 (3-day continuous iv infusion …
Abstract
Background: UCN-01, a Chk1 inhibitor, abrogates S and G2 arrest and enhances cancer cell killing by DNA-damaging drugs in preclinical models. UCN-01 avidly binds α1-acid glycoprotein in plasma; whether sufficient drug concentrations are achieved in human tumors is unknown. A phase I trial tested the hypothesis that UCN-01 abrogates cisplatin-induced cell cycle arrest (in tumors) at tolerable doses.
Methods: Patients with advanced cancer received i.v. cisplatin, followed 22 hours later by UCN-01 (3-day continuous i.v. infusion of a 28-day cycle). Platinum was measured by atomic absorption, UCN-01 by high-performance liquid chromatography, and cell cycle progression in tumor biopsies by geminin immunostaining (biomarker for S/G2 phases of cell cycle).
Results: The first two patients treated with cisplatin (20 mg/m2 plus UCN-01 45 mg/m2/d) experienced dose-limiting toxicities (subarachnoid hemorrhage, hyperglycemia, hypoxia, cardiac ischemia, and atrial fibrillation). Following 25% UCN-01 dose reduction, no toxicities greater than grade 2 were seen. Median plasma UCN-01 half-life (T1/2) was 405 hours. Salivary UCN-01 concentrations showed a rapid initial decline (median T1/2α, 29.9 hours), followed by a terminal decay parallel to that in plasma. UCN-01 pharmacokinetics, and the timing of clinical toxicities, suggests that UCN-01 is bioavailable despite α1-acid glycoprotein binding. Marked suppression of cells in S/G2 in tumor biopsies was seen by geminin immunohistochemistry, suggesting that UCN-01 is bioavailable at concentrations sufficient to inhibit Chk1.
Conclusions: Cisplatin (30 mg/m2), followed 22 hours later by UCN-01 (34 mg/m2/d for 3 days), is well tolerated clinically and yields UCN-01 concentrations sufficient to affect cell cycle progression in tumors.
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