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Modulation of Cell Cycle Progression in Human Tumors: A Pharmacokinetic and Tumor Molecular Pharmacodynamic Study of Cisplatin Plus the Chk1 Inhibitor UCN-01 (NSC 638850)

Authors' Affiliations: ¹ Sections of Hematology/Oncology and ² Clinical Pharmacology, Departments of Medicine, ³ Pathology, and ⁴ Pharmacology, Dartmouth Medical School, Norris Cotton Cancer Center, Lebanon, New Hampshire

Requests for reprints: Raymond P. Perez, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756. Phone: 603-650-6633; Fax: 603-650-7791; E-mail: Raymond.Perez{at}Dartmouth.edu.

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 1-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 (T_1/2) was 405 hours. Salivary UCN-01 concentrations showed a rapid initial decline (median T_1/2, 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 1-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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