Aphidicolin markedly increases the platinum sensitivity of cells from primary ovarian tumours.

Abstract

Enhanced DNA repair has been observed in cisplatin-resistant ovarian cancer cell lines. This resistance can be modulated, on co-incubation with aphidicolin in established cell lines and animal tumour models, by inhibiting DNA polymerases. We describe a study of the in vitro modulation effect of aphidicolin on cisplatin and carboplatin using fresh cells harvested from biopsy samples or ascitic fluids from 25 patients with ovarian adenocarcinoma. The MTT assay was used to measure cell survival after drug exposure. Aphidicolin (up to 30 microM) showed no cytotoxicity when tested alone. Forty-seven comparisons were made between drug with and without aphidicolin, and 37 (79%) cases demonstrated a significant increase in sensitivity to the platinum agents on co-incubation. Overall, there was a median 10-fold (range 1.64- to 58.5-fold) increase in sensitivity. When patients were grouped according to in vitro sensitivity to platinum, aphidicolin had a significantly greater effect in the "resistant' group, causing a median 13.5-fold increase in sensitivity compared with 2.4-fold in the "sensitive' group. Furthermore, a positive correlation between the LC50 for platinum and the corresponding fold increase in sensitivity suggests that aphidicolin overcomes platinum resistance in fresh cells from primary tumours. These results encourage the further development of this interesting compound.