GEMCITABINE-CARBOPLATIN MECHANISM OF SYNERGY

Clin Cancer Res. 2010 Aug 18. [Epub ahead of print]
Inhibition of carboplatin-induced DNA interstrand crosslink repair by gemcitabine in patients receiving these drugs for 'platinum-resistant' ovarian cancer.
Ledermann JA, Gabra H, Jayson GC, Spanswick VJ, Rustin GJ, Jitlal M, James L, Hartley JA.

UCL Cancer Institute, University College London.
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 (PBLs) were sampled after drug administration to measure DNA interstrand crosslink formation and repair.

PATIENTS AND METHODS: 40 patients received carboplatin AUC4 followed by gemcitabine 1000 mg/m2 with a second dose of gemcitabine on day 8. PBLs were obtained in 12 patients before, and at intervals during the first cycle of chemotherapy. DNA crosslink 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% (RECIST 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 crosslinking was seen by 24 hours. Significant reduction was seen in the repair of in vivo carboplatin-induced DNA crosslinks 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 crosslinks. Future studies should explore co-administration of these drugs, as this may be a more effective schedule.