Modulation of drug resistance mediated by loss of mismatch repair by the DNA polymerase inhibitor aphidicolin

Loss of expression of mismatch repair (MMR) proteins leads to resistance of tumor cells to a variety of DNA-damaging agents, including bifunctional al kylating and monofunctional methylating agents such as cis-diaminedichlorop latinum II (CDDP) and N' -methyl-N-nitrosourea (MNU). It has been suggested that coupling to cell death does not occur in the absence of MMR, but inst ead, DNA lesions are bypassed during replication, giving a drug-tolerant ph enotype, In the present study, we have used aphidicolin (Ap), an inhibitor of DNA polymerases, to study the role of replicative bypass in drug resista nce mediated by loss of MMR, We have examined the survival of matched ovari an carcinoma cell lines with known MMR status after sequential treatment wi th CDDP or MNU and Ap We show that Ap increases the sensitivity of MMR-defi cient cell lines to CDDP and MNU to a greater extent than their MMR-profici ent counterparts. Furthermore, loss of Mh IR correlates with loss of CDDP-i nduced G(2) arrest, but this is partially restored after lip treatment. The se data support Ap sensitizing drug-resistant cancer cells that have lost M MR to CDDP and MNU and suggest that the potential use of Ap as a modulator of drug resistance should be targeted to MMR-defective tumors.