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Research Articles: Therapeutics, Targets, and Development

Chemotherapeutic selectivity conferred by selenium: a role for p53-dependent DNA repair

¹ Department of Microbiology and Walther Oncology Center, Indiana University Cancer Center, and ² Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine; and ³ Walther Cancer Institute, Indianapolis, Indiana

Requests for reprints: Martin L. Smith, Indiana University Cancer Center, Indiana University School of Medicine, Room 155, 1044 West Walnut Street, Indianapolis, IN 46202. Phone: 317-278-0225; Fax: 317-274-7592. E-mail: marlsmit{at}iupui.edu

Abstract

Selenium in various chemical forms has been the subject of cancer chemoprevention trials, but, more recently, selenium has been used in combination with DNA-damaging chemotherapeutics. Specifically, selenium protected tissues from dose-limiting toxicity and, in fact, allowed delivery of higher chemotherapeutic doses. At the same time, selenium did not protect cancer cells. Therefore, we seek to define the genetic basis for the observed selectivity of selenium in combination chemotherapeutics. The tumor suppressor p53 is mutated in the vast majority of cancers, but is by definition wild-type in nontarget tissues such as bone marrow and gut epithelium, tissues that are often dose-limiting due to DNA damage. We used primary, low-passage mouse embryonic fibroblasts that are wild-type or null for p53 genes to test differential effects of selenium. Seleno-L-methionine, nontoxic by itself, was used to pretreat cell cultures before exposure to UV radiation or UV-mimetic cancer chemotherapy drugs. Seleno-L-methionine pretreatment caused a DNA repair response, which protected from subsequent challenge with DNA-damaging agents. The observed DNA repair response and subsequent DNA damage protection were p53 dependent as neither was observed in p53-null cells. The data suggest that (a) p53 may be an important genetic determinant that distinguishes normal cells from cancer cells, and (b) combinatorial chemotherapeutics that act by p53-dependent mechanisms may enhance chemotherapeutic efficacy by increasing the chemotherapeutic window distinguishing cancer cells from normal cells. [Mol Cancer Ther 2007;6(1):355–61]

Grant support: U.S. Department of Defense, American Cancer Society, American Institute for Cancer Research, Indiana University Cancer Center.

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.

Received 8/ 7/06; revised 11/ 1/06; accepted 11/28/06.