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

Molecular Cancer Therapeutics
S M HillierR G Croy

Abstract

The multifunctional molecule 11beta-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 11beta-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 11beta-DNA adducts in tumor xenograft and nontumor tissues in mice. Using [14C]-11beta-dichloro, we show that the molecule remains intact in blood and is widely distributed in mouse tissues after i.p. injection. Covalent 11beta-guanine adducts identified in DNA that had been allowed to react with 11beta-dichloro in vitro were also found in DNA isolated from cells in culture treated with 11beta-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]-11beta-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 micromol/L ...Continue Reading

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Citations

Nov 1, 2011·Journal of the American Chemical Society·Yunyan KuangXiaohua Peng
Apr 23, 2013·AIDS Research and Human Retroviruses·Nicolette A LouissaintCraig W Hendrix
Nov 19, 2010·Bioanalysis·Paul T Henderson, Chong-Xian Pan
Jan 27, 2016·Dalton Transactions : an International Journal of Inorganic Chemistry·Subhendu KarmakarArindam Mukherjee
Oct 24, 2013·Journal of Medicinal Chemistry·Melissa MillardNouri Neamati
Jun 28, 2017·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Jing-Xiang ZhangCheng-Yong Su

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