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)

• Published in: Clinical cancer research Vol. 12; no. 23; pp. 7079 - 7085
• Main Authors: PEREZ, Raymond P, LEWIS, Lionel D, BEELEN, Andrew P, OLSZANSKI, Anthony J, JOHNSTON, Nicholas, RHODES, C. Harker, BEAULIEU, Bernard, ERNSTOFF, Marc S, EASTMAN, Alan
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.12.2006
• Subjects: Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; biomarker; Biopsy, Fine-Needle; cell cycle; Cell Cycle - drug effects; cisplatin; Cisplatin - administration & dosage; Cisplatin - adverse effects; Cisplatin - pharmacokinetics; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Follow-Up Studies; geminin; Humans; Injections, Intravenous; Maximum Tolerated Dose; Medical sciences; Neoplasms - diagnosis; Neoplasms - drug therapy; pharmacodynamics; pharmacokinetics; Pharmacology. Drug treatments; phase I clinical trial; Predictive Value of Tests; Staurosporine - administration & dosage; Staurosporine - adverse effects; Staurosporine - analogs & derivatives; Staurosporine - pharmacokinetics; Tissue Distribution; Treatment Outcome; UCN-01; α1-acid glycoprotein (AAG); Antineoplastic agent; Human; Pharmacodynamics; Malignant tumor; Biological activity; Cisplatin; Alkylating agent; Modulation; Checkpoint kinase 1; Cell cycle; Tumor progression; Inhibitor; Pharmacokinetics; Platinum II Complexes
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-06-0197

Background: UCN-01, a Chk1 inhibitor, abrogates S and G 2 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/G 2 phases of cell cycle). Results: The first two patients treated with cisplatin (20 mg/m 2 plus UCN-01 45 mg/m 2 /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 1/2α , 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/G 2 in tumor biopsies was seen by geminin immunohistochemistry, suggesting that UCN-01 is bioavailable at concentrations sufficient to inhibit Chk1. Conclusions: Cisplatin (30 mg/m 2 ), followed 22 hours later by UCN-01 (34 mg/m 2 /d for 3 days), is well tolerated clinically and yields UCN-01 concentrations sufficient to affect cell cycle progression in tumors.