Effect of fluconazole on the growth and adhesion of Candida albicans in the presence of antineoplastic agents

Abstract

The effect of fluconazole and the antineoplastic agents etoposide and methotrexate on the growth and adhesion of Candida albicans were studied. All the tested chemicals inhibited the growth and the adhesion of the yeast to buccal epithelial cells, while fluconazole and etoposide inhibited the adhesion to acrylate surface as well. Our experiments also demonstrated that etoposide and methotrexate interfered with the inhibitory effect of fluconazole on both the growth and cell adhesion. While etoposide strengthened the inhibitory effect of fluconazole, in the presence of methotrexate fluconazole showed lower inhibition on both the growth and adhesion.

Antifolates as antimycotics?

“…For example, because of the increasing susceptibility of patients with advanced cancer to fungal infections, cancer chemotherapeutic and antifungal agents are often given concomitantly. Previous work showed that in the presence of MTX, fluconazole showed lower inhibition of both growth and adhesion of C. albicans [11], suggesting an antagonistic effect of both drugs. In contrast, here we show that MTX and azole drugs acts indifferently or synergistically when used to treat the yeast or hyphal form of C. albicans, respectively.…”

“…In contrast, here we show that MTX and azole drugs acts indifferently or synergistically when used to treat the yeast or hyphal form of C. albicans, respectively. Probably, the different results obtained by Fekete-Forgács et al [11] were due to the experimental conditions used in their assays. The high MTX concentrations used for the synergy experiments (up to 2.5 mg/mL) would favour drug-drug interactions; in fact, when we tried to repeat this experiment we found a milky precipitate (with a high absorption at 640 nm) even in the absence of C. albicans.…”

“…However, MTX is an example of a drug that shows potent binding to an important target enzyme in vitro but is not necessarily effective in vivo. Several reports have demonstrated that MTX shows no anticandidal activity [11] and we have shown that the MIC for 50% of the tested strains (MIC 50 ) of C. albicans in the yeast state was >2048 g/mL (Table 1). Yeast resistance to MTX could be mediated by the permeability barrier and/or efflux pumps or by the presence of naturally insensitive DHFR.…”

“…In fact, C. albicans is a eukaryotic organism and expresses a TMP-insensitive DHFR that is closely similar to the mammalian enzyme. On the other hand, MTX, which is a potent inhibitor of C. albicans DHFR [10], shows no detectable anticandidal activity [11]. Recently, we have shown that a tea polyphenol, epigallocatechin-3-gallate, inhibited ergosterol biosynthesis by disturbing folic acid metabolism in C. albicans [12].…”

Antifungal activity of nontraditional antifungal agents

“…When combined with fl uconazole in vitro, etoposide enhanced the inhibitory activity of fl uconazole against C. albicans, whereas methotrexate antagonized fl uconazole's effect. Both agents inhibited adhesion of C. albicans to buccal epithelial cells [17]. Multiple other agents, such as mitomycin C, doxorubicin, and 5-fl uorouracil, have demonstrated activity against yeasts as well.…”