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Research Articles: Therapeutics, Targets, and Development

Novel E-ring camptothecin keto analogues (S38809 and S39625) are stable, potent, and selective topoisomerase I inhibitors without being substrates of drug efflux transporters

¹ Laboratory of Molecular Pharmacology and ² Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland and ³ Institut de Recherches Servier, Croissy sur Seine, France

Requests for reprints: Yves Pommier, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, 37 Convent Drive, Building 37, Room 5068, Bethesda, MD 20892-4255. Phone: 301-496-5944; Fax: 301-402-0752. E-mail: pommier{at}nih.gov

Abstract

Camptothecin (CPT) analogues are powerful anticancer agents but are chemically unstable due to their -hydroxylactone six-membered E-ring structure, which is essential for trapping topoisomerase I (Top1)-DNA cleavage complexes. To stabilize the E-ring, CPT keto analogues with a five-membered E-ring lacking the oxygen of the lactone ring (S38809 and S39625) have been synthesized. S39625 has been selected for advanced preclinical development based on its promising activity in tumor models. Here, we show that both keto analogues are active against purified Top1 and selective against Top1 in yeast and human cancer cells. The keto analogues show improved cytotoxicity toward colon, breast, and prostate cancer cells and leukemia cells compared with CPT. The drug-induced Top1-DNA cleavage complexes induced by the keto analogues show remarkable persistence both with purified Top1 and in cells following 1-h drug treatments. Moreover, we find that S39625 is not a substrate for either the ABCB1 (multidrug resistance-1/P-glycoprotein) or ABCG2 (mitoxantrone resistance/breast cancer resistance protein) drug efflux transporters, which sets S39625 apart from the clinically used CPT analogues topotecan or SN-38 (active metabolite of irinotecan). Finally, we show that nanomolar concentrations of S38809 or S39625 induce intense and persistent histone -H2AX. The chemical stability of the keto analogues and the ability of S39625 to produce high levels of persistent Top1-DNA cleavage complex and its potent antiproliferative activity against human cancer cell lines make S39625 a promising new anticancer drug candidate. Histone -H2AX could be used as a biomarker for the upcoming clinical trials of S39625. [Mol Cancer Ther 2007;6(12):3229–38]

Grant support: Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ J. Hickman, Institut de Recherches Servier, personal communication.

⁵ U.S. patent 6-509-345 G. Lavielle et al.

⁶ Unpublished crystal structure results from Dr. Lance Stewart and coworkers at DeCode Biostructures, Brainbridge Island, WA, and our own molecular docking results.

Received 7/ 2/07; revised 9/24/07; accepted 10/17/07.

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