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Clin Cancer Res. 2006 Dec 1;12(23):7079-85.

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).

Author information

1
Section of Hematology/Oncology, Department of Medicine, Dartmouth Medical School, Norris Cotton Cancer Center, Lebanon, New Hampshire 03756, USA. Raymond.Perez@Dartmouth.edu

Abstract

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 alpha1-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(1/2alpha), 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 alpha1-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.

PMID:
17145831
DOI:
10.1158/1078-0432.CCR-06-0197
[Indexed for MEDLINE]
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