APHIDICOLIN MARKEDLY INCREASES THE PLATINUM SENSITIVITY OF CELLS FROMPRIMARY OVARIAN-TUMORS

Enhanced DNA repair has been observed in cisplatin-resistant ovarian c ancer cell lines. This resistance can be modulated, on co-incubation w ith aphidicolin in established cell lines and animal tumour models, by inhibiting DNA polymerases. We describe a study of the in vitro modul ation effect of aphidicolin on cisplatin and carboplatin using fresh c ells harvested from biopsy samples or ascitic fluids from 25 patients with ovarian adenocarcinoma. The MTT assay was used to measure cell su rvival after drug exposure. Aphidicolin (up to 30 mu M) showed no cyto toxicity when tested alone. Forty-seven comparisons were made between drug with and without aphidicolin, and 37 (79%) cases demonstrated a s ignificant increase in sensitivity to the platinum agents on co-incuba tion. Overall, there was a median 10-fold (range 1.64- to 58.5-fold) i ncrease in sensitivity. When patients were grouped according to in vit ro sensitivity to platinum, aphidicolin had a significantly greater ef fect in the 'resistant' group, causing a median 13.5-fold increase in sensitivity compared with 2.4-fold in the 'sensitive' group. Furthermo re, a positive correlation between the LC(50) for platinum and the cor responding fold increase in sensitivity suggests that aphidicolin over comes platinum resistance in fresh cells from primary tumours. These r esults encourage the further development of this interesting compound.