TY - JOUR
T1 - Modulation of cell cycle progression in human tumors
T2 - A pharmacokinetic and tumor molecular pharmacodynamic study of cisplatin plus the Chk1 inhibitor UCN-01 (NSC 638850)
AU - Perez, Raymond P.
AU - Lewis, Lionel D.
AU - Beelen, Andrew P.
AU - Olszanski, Anthony J.
AU - Johnston, Nicholas
AU - Rhodes, C. Harker
AU - Beaulieu, Bernard
AU - Ernstoff, Marc S.
AU - Eastman, Alan
PY - 2006/12/1
Y1 - 2006/12/1
N2 - 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.
AB - 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.
KW - Antineoplastic Combined Chemotherapy Protocols/adverse effects
KW - Biopsy, Fine-Needle
KW - Cell Cycle/drug effects
KW - Cisplatin/administration & dosage
KW - Disease Progression
KW - Dose-Response Relationship, Drug
KW - Drug Administration Schedule
KW - Follow-Up Studies
KW - Humans
KW - Injections, Intravenous
KW - Maximum Tolerated Dose
KW - Neoplasms/diagnosis
KW - Predictive Value of Tests
KW - Staurosporine/administration & dosage
KW - Tissue Distribution
KW - Treatment Outcome
UR - http://www.scopus.com/inward/record.url?scp=33746388284&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000242691000031&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1158/1078-0432.CCR-06-0197
DO - 10.1158/1078-0432.CCR-06-0197
M3 - Article
C2 - 17145831
SN - 1078-0432
VL - 12
SP - 7079
EP - 7085
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 23
ER -