The cyclin-dependent kinase inhibitor flavopiridol potentiates doxorubicin efficacy in advanced sarcomas: preclinical investigations and results of a phase I dose-escalation clinical trial

Luke, J. J., D'Adamo, D. R., Dickson, M. A., Keohan, M. L., Carvajal, R. D., Maki, R. G., de Stanchina, E., Musi, E., Singer, S., Schwartz, G. K. (May 2012) The cyclin-dependent kinase inhibitor flavopiridol potentiates doxorubicin efficacy in advanced sarcomas: preclinical investigations and results of a phase I dose-escalation clinical trial. Clin Cancer Res, 18 (9). pp. 2638-47. ISSN 1078-0432 (Print)1078-0432 (Linking)

URL: https://www.ncbi.nlm.nih.gov/pubmed/22374332
DOI: 10.1158/1078-0432.CCR-11-3203

Abstract

PURPOSE: Dysregulated cyclin-dependent kinases are important to the growth of some sarcomas. Flavopiridol is a pan-CDK inhibitor that has been shown to potentiate chemotherapy. As such, we explored the potentiation of doxorubicin by flavopiridol in sarcoma, in vitro and in vivo, and conducted a phase I trial of flavopiridol with doxorubicin in patients with advanced sarcomas. EXPERIMENTAL DESIGN: Sarcoma cell lines and xenografts were treated with flavopiridol alone and in combination with doxorubicin. In the phase I study, doxorubicin and flavopiridol were administered on two flavopiridol schedules; a 1-hour bolus and split dosing as a 30-minute bolus followed by a 4-hour infusion. RESULTS: Preclinically, flavopiridol potentiated doxorubicin. In vivo, doxorubicin administered 1 hour before flavopiridol was more active than doxorubicin alone. Clinically, 31 patients were enrolled on protocol and flavopiridol was escalated to target dose in two schedules (90 mg/m(2) bolus; 50 mg/m(2) bolus + 40 mg/m(2) infusion) both in combination with doxorubicin (60 mg/m(2)). Dose-limiting toxicities were neutropenia, leukopenia, and febrile neutropenia but no maximum tolerated dose was defined. Flavopiridol pharmacokinetics showed increasing C(max) with increasing dose. Response Evaluation Criteria in Solid Tumors (RECIST) responses included two partial responses, however, stable disease was seen in 16 patients. Of 12 evaluable patients with progressive well- and dedifferentiated liposarcoma, eight had stable disease greater than 12 weeks. CONCLUSIONS: The sequential combination of doxorubicin followed by flavopiridol is well tolerated on both schedules. Disease control was observed in well- and dedifferentiated liposarcoma specifically, a disease in which CDK4 is known to be amplified.

Item Type: Paper
Uncontrolled Keywords: Adult Aged Animals Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics/*therapeutic use Cyclin-Dependent Kinases/*antagonists & inhibitors Dose-Response Relationship, Drug Doxorubicin/administration & dosage Drug Evaluation, Preclinical Female Flavonoids/administration & dosage Humans Immunoblotting Male Maximum Tolerated Dose Mice Mice, SCID Middle Aged Neoplasm Grading Nerve Sheath Neoplasms/*drug therapy Piperidines/administration & dosage Sarcoma/*drug therapy Tissue Distribution
Subjects: diseases & disorders > cancer > drugs and therapies
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase
diseases & disorders > cancer > cancer types > sarcoma
CSHL Authors:
Communities: CSHL labs > Maki lab
Depositing User: Matt Covey
Date: 1 May 2012
Date Deposited: 20 Oct 2016 18:41
Last Modified: 20 Oct 2016 18:41
PMCID: PMC3343204
Related URLs:
URI: http://repository.cshl.edu/id/eprint/33741

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