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.

Figure 1. Treatment and Blood sampling schema. C= Carboplatin; G= Gemcitabine

Figure 2. Overall survival (a) and Progression-free survival (b)

Figure 2. Overall survival (a) and Progression-free survival (b)

Figure 3. Formation and repair of carboplatin-induced DNA interstrand crosslinks in PBLs taken from 12 patients following treatment with carboplatin (a) and then in a sample taken after the administration of gemcitabine following carboplatin (b).

Results are expressed as percentage decrease in tail moment and the horizontal bars and numbers indicate the median values.

Figure 3. Formation and repair of carboplatin-induced DNA interstrand crosslinks in PBLs taken from 12 patients following treatment with carboplatin (a) and then in a sample taken after the administration of gemcitabine following carboplatin (b).

Results are expressed as percentage decrease in tail moment and the horizontal bars and numbers indicate the median values.

Figure 4. Percentage repair of carboplatin-induced DNA interstrand crosslinks in patient PBLs at 48 hours in the blood samples taken after treatment with carboplatin alone and after treatment with the combination of carboplatin and gemcitabine.

Horizontal bars indicate median values.