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).
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.
Perez
Raymond P
RP
Section of Hematology/Oncology, Department of Medicine, Dartmouth Medical School, Norris Cotton Cancer Center, Lebanon, New Hampshire 03756, USA. Raymond.Perez@Dartmouth.edu
Lewis
Lionel D
LD
Beelen
Andrew P
AP
Olszanski
Anthony J
AJ
Johnston
Nicholas
N
Rhodes
C Harker
CH
Beaulieu
Bernard
B
Ernstoff
Marc S
MS
Eastman
Alan
A
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D044963:Biopsy, Fine-Needle; D002453:Cell Cycle / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005500:Follow-Up Studies; D006801:Humans; D007275:Injections, Intravenous; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D011237:Predictive Value of Tests; D019311:Staurosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D016896:Treatment Outcome
C054852:7-hydroxystaurosporine; D019311:Staurosporine; D002945:Cisplatin