Pharmacology

Mixing and Matching

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Science  04 Jul 2003:
Vol. 301, Issue 5629, pp. 21
DOI: 10.1126/science.301.5629.21b

The reductionist philosophy within molecular and cellular biology has dominated the past several decades, but systems-level analyses are making a comeback, empowered by the advent of large data sets: genome sequences, RNA microarrays, and proteomic maps. Extending this resurgence to drug discovery, Borisy et al. describe an analysis of binary combinations of agents that, when administered together, display a therapeutic efficacy greater than the sum of the single components.

To combat the problem of increasing resistance to antifungal drugs, they pair fluconazole with phenazopyridine (a urinary tract analgesic) and observe a fungicidal effect on a resistant strain of Candida albicans; this synergy appears to be due to the potent inhibition of the multidrug resistance pump. A second instance of unpredictably cooperative drugs involves the antipsychotic chlorpromazine and the antiprotozoal pentamidine. Neither is potent on its own, yet this pair inhibited the growth of A549 lung carcinoma cells in a mouse model more effectively than paclitaxel, an anticancer drug that is used clinically. It does not seem beyond belief that the development of multidrug cocktails aimed at several targets may, in fact, herald a re-evaluation of so-called folk medicine mixtures concocted by trial and error over many generations. — GJC

Proc. Natl. Acad. Sci. U.S.A. 100, 7977 (2003).

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