Inhibition of carboplatin-induced DNA interstrand cross-link repair by gemcitabine in patients receiving these drugs for platinum-resistant ovarian cancer.

Abstract

BACKGROUND:

The potential of gemcitabine to interact with carboplatin was explored in a phase II trial in platinum-resistant ovarian cancer. Peripheral blood lymphocytes were sampled after drug administration to measure DNA interstrand cross-link formation and repair.

PATIENTS AND METHODS:

Forty patients received carboplatin target area under concentration-time curve (AUC 4) followed by gemcitabine 1,000 mg/m(2) with a second dose of gemcitabine on day 8. Peripheral blood lymphocytes were obtained in 12 patients before and at intervals during the first cycle of chemotherapy. DNA cross-link formation and repair (unhooking) were measured by the single-cell gel electrophoresis (comet) assay following ex vivo incubation.

RESULTS:

The global response rate was 47% (Response Evaluation Criteria in Solid Tumors rate, 29%; CA125 rate, 63%). Delays in treatment were seen in 24% of cycles largely due to myelosuppression; 15% of day 8 administration was omitted. Peak carboplatin-induced DNA cross-linking was seen by 24 hours. Significant reduction was seen in the repair of in vivo carboplatin-induced DNA cross-links following administration of gemcitabine.

CONCLUSION:

An enhanced activity of carboplatin in platinum-resistant ovarian cancer may be due to synergy with gemcitabine through inhibition of repair of DNA cross-links. Future studies should explore coadministration of these drugs, as this may be a more effective schedule.

• Authors: Jonathan A Ledermann, Hani Gabra, Gordon C Jayson, Victoria J Spanswick, Gordon J S Rustin, Mark Jitlal, Lindsay E James, John A Hartley
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 19 Pg. 4899-905 (Oct 01 2010) ISSN: 1557-3265 [Electronic] United States
• PMID: 20719935 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2010 AACR.

Chemical References

• Antineoplastic Agents
• DNA, Neoplasm
• Platinum Compounds
• Deoxycytidine
• Carboplatin
• Gemcitabine

Topics

• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacology, therapeutic use)
• Carboplatin (administration & dosage, antagonists & inhibitors, pharmacology, therapeutic use)
• DNA Damage
• DNA Repair (drug effects)
• DNA, Neoplasm (metabolism)
• Deoxycytidine (administration & dosage, adverse effects, analogs & derivatives, pharmacology, therapeutic use)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm (drug effects)
• Female
• Humans
• Middle Aged
• Ovarian Neoplasms (drug therapy)
• Platinum Compounds (pharmacology, therapeutic use)
• Time Factors
• Treatment Outcome
• Gemcitabine