Systematic discovery of multicomponent therapeutics

被引：460

作者：

Borisy, AA ^{[1
]}

Elliott, PJ ^{[1
]}

Hurst, NW ^{[1
]}

Lee, MS ^{[1
]}

Lehár, J ^{[1
]}

Price, ER ^{[1
]}

Serbedzija, G ^{[1
]}

Zimmermann, GR ^{[1
]}

Foley, MA ^{[1
]}

Stockwell, BR ^{[1
]}

Keith, CT ^{[1
]}

机构：

[1] CombinatoRx Inc, Boston, MA 02118 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2003年 / 100卷 / 13期

关键词：

D O I：

10.1073/pnas.1337088100

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Multicomponent therapies, originating through deliberate mixing of drugs in a clinical setting, through happenstance, and through rational design, have a successful history in a number of areas of medicine, including cancer, infectious diseases, and CNS disorders. We have developed a high-throughput screening method for identifying effective combinations of therapeutic compounds. We report here that systematic screening of combinations of small molecules reveals unexpected interactions between compounds, presumably due to interactions between the pathways on which they act. Through systematic screening of approximate to120,000 different two-component combinations of reference-listed drugs, we identified potential multicomponent therapeutics, including (i) fungistatic and analgesic agents that together generate fungicidal activity in drug-resistant Candida albicans,yet do not significantly affect human cells, (ii) glucocorticoid and antiplatelet agents that together suppress the production of tumor necrosis factor-a in human primary peripheral blood mononuclear cells, and (iii) antipsychotic and antiprotozoal agents that do not exhibit significant antitumor activity alone, yet together prevent the growth of tumors in mice. Systematic combination screening may ultimately be useful for exploring the connectivity of biological pathways and, when performed with reference-listed drugs, may result in the discovery of new combination drug regimens.

引用

页码：7977 / 7982

页数：6

共 46 条

[1] Effects of pentamidine on polyamine level and biosynthesis in wild-type, pentamidine-treated, and pentamidine-resistant Leishmania [J].