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Research Articles: Therapeutics

DNA adducts formed by a novel antitumor agent 11ß-dichloro in vitro and in vivo

¹ Department of Chemistry and Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, Massachusetts and ² School of Environmental Affairs, Universidad Metropolitana, San Juan, Puerto Rico

Requests for reprints: Robert G. Croy, Department of Chemistry and Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, MA 02139. Phone: 617-253-6729; Fax: 617-253-5445. E-mail: rgcroy{at}mit.edu

Abstract

The multifunctional molecule 11ß-dichloro consists of a ligand for the androgen receptor linked to a bifunctional alkylating group, permitting it to create DNA adducts that bind the androgen receptor. We propose that binding of the androgen receptor to 11ß-DNA adducts acts to both shield damaged sites from repair and disrupt the expression of genes essential for growth and survival. We investigated the formation 11ß-DNA adducts in tumor xenograft and nontumor tissues in mice. Using [¹⁴C]-11ß-dichloro, we show that the molecule remains intact in blood and is widely distributed in mouse tissues after i.p. injection. Covalent 11ß-guanine adducts identified in DNA that had been allowed to react with 11ß-dichloro in vitro were also found in DNA isolated from cells in culture treated with 11ß-dichloro as well as in DNA isolated from liver and tumor tissues of mice treated with the compound. We used accelerator mass spectrometry to determine the levels of [¹⁴C]-11ß-DNA adducts in LNCaP cells treated in culture as well as in liver tissue and LNCaP xenograft tumors in treated mice. The level of DNA adducts in tumor tissue was found to be similar to that found in LNCaP cells in culture treated with 2.5 µmol/L 11ß-dichloro. Our results indicate that 11ß-dichloro has sufficient stability to enter the circulation, penetrate tissues, and form DNA adducts that are capable of binding the androgen receptor in target tissues in vivo. These data suggest the involvement of our novel mechanisms in the antitumor effects of 11ß-dichloro. [Mol Cancer Ther 2006;5(4):977–84]

Grant support: Department of Defense grant DAMD 17-03-1-0085 and NIH grants R01 CA 77743-06 (J.M. Essigmann) and P30-ES02109 (Massachusetts Institute of Technology Center for Environmental Health Sciences).

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 11/ 8/05; revised 1/ 2/06; accepted 2/15/06.