Modification of responses of Candida albicans to cisplatin by membrane damaging antimycotic agents

The genotoxic, antineoplastic platinum coordination complex, cisplatin (cis-diamminedichloroplatinum (II], exists as a positively charged aquated complex in water solution and as a neutral, nonaquated complex in saline solution. Candida albicans exhibited greater susceptibilities to cellular inactivation and induction of mitotic recombination when treated with the aquated rather than the nonaquated drug. The differential in responses was expressed by cells grown after treatment at 37 degrees C or at 25 degrees C, a temperature which promotes recovery from DNA damages by the yeast generally. Studies with protoplasts established that cell wall components do not influence cellular reactions to either form of the drug. However, membrane damaging antimycotic agents markedly affected responses. Pretreatments with fungistatic ketoconazole or with miconazole, under fungistatic or fungicidal conditions, enhanced cellular resistance to inactivation by aquated cisplatin: the effect was more pronounced with post-cisplatin growth at 25 degrees C than 37 degrees C. Fungicidal pretreatments with amphotericin B or miconazole greatly increased susceptibilities of surviving cells to the lethal and recombinagenic effects of nonaquated cisplatin with post-cisplatin recovery at 25 degrees C or 37 degrees C. Possible mechanisms underlying these responses and their implications for stability of C. albicans populations in cancer patients undergoing therapy with cisplatin are discussed.