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)

Raymond P. Perez, Lionel D. Lewis, Andrew P. Beelen, Anthony J. Olszanski, Nicholas Johnston, C. Harker Rhodes, Bernard Beaulieu, Marc S. Ernstoff, Alan Eastman

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

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/m 2 plus UCN-01 45 mg/m2/d) experienced dose-limiting toxicities (subarachnoid hemorrhage, hyperglycemic, 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/m 2/d for 3 days), is well tolerated clinically and yields UCN-01 concentrations sufficient to affect cell cycle progression in tumors.

Original languageEnglish
Pages (from-to)7079-7085
Number of pages7
JournalClinical Cancer Research
Volume12
Issue number23
DOIs
StatePublished - Dec 1 2006

Keywords

  • Antineoplastic Combined Chemotherapy Protocols/adverse effects
  • Biopsy, Fine-Needle
  • Cell Cycle/drug effects
  • Cisplatin/administration & dosage
  • Disease Progression
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Follow-Up Studies
  • Humans
  • Injections, Intravenous
  • Maximum Tolerated Dose
  • Neoplasms/diagnosis
  • Predictive Value of Tests
  • Staurosporine/administration & dosage
  • Tissue Distribution
  • Treatment Outcome

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