Antifungal activities of antineoplastic agents Saccharomyces cerevisiae asa model system to study drug action

Recent evolutionary studies reveal that microorganisms including yeasts and fungi are more closely related to mammals than was previously appreciated. Possibly as a consequence, many natural-product toxins that have antimicro bial activity are also toxic to mammalian cells. While this makes it diffic ult to discover antifungal agents without toxic side effects, it also has e nabled detailed studies of drug action in simple genetic model systems. We review here studies on the antifungal actions of antineoplasmic agents. Top ics covered include the mechanisms of action of inhibitors of topoisomerase s I and II; the immunosuppressants rapamycin, cyclosporin A, and FK506; the phosphatidylinositol 3-kinase inhibitor wortmannin; the angiogenesis inhib itors fumagillin and ovalicin; the HSP90 inhibitor geldanamycin; and agents that inhibit sphingolipid metabolism. In general, these natural products i nhibit target proteins conserved from microorganisms to humans. These studi es highlight the potential of microorganisms as screening tools to elucidat e the mechanisms of action of novel pharmacological agents with unique effe cts against specific mammalian cell types, including neoplastic cells. In a ddition, this analysis suggests that antineoplastic agents and derivatives might find novel indications in the treatment of fungal infections, for whi ch few agents are presently available, toxicity remains a serious concern, and drug resistance is emerging.