Inhibition of DNA repair in cells treated with a combination of alkylating agents.

Aphidicolin (AP) or hydroxyurea (HU) inhibited DNA repair and enhanced cytotoxicity in human ovarian carcinoma cells A2780 treated with L-phenylalanine mustard (L-PAM) combined with cisplatin or thioTEPA, and in the cells treated with cisplatin combined with thioTEPA. In cultures treated with L-PAM or cisplatin alone post-treatment with AP or HU had no effect on DNA repair and produced only additive cytotoxicity. Post-treatment with AP + HU inhibited DNA repair and enhanced cell killing in cultures treated with L-PAM alone. The inhibitor of protein synthesis cycloheximide protected cells from the cytotoxicity of AP + HU but had no effect on synergistic cell killing produced by DNA repair inhibition. In cisplatin-resistant cells A2780/CP post-treatment with AP + HU enhanced the cytotoxicity of L-PAM, but not of cisplatin. However, in resistant cells treated with cisplatin combined with L-PAM or thioTEPA DNA repair inhibitors decreased IC90 of cisplatin. Treatment of cells with two alkylating agents enhanced the sensitivity to DNA repair inhibitors and eliminated low sensitivity to inhibitors of repair associated with drug resistance.