DNA adducts formed by a novel antitumor agent 11beta-dichloro in vitro and in vivo.
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 11beta-dichloro. Our results indicate that 11beta-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 11beta-dichloro.
Hillier
Shawn M
SM
Department of Chemistry and Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Marquis
John C
JC
Zayas
Beatriz
B
Wishnok
John S
JS
Liberman
Rosa G
RG
Skipper
Paul L
PL
Tannenbaum
Steven R
SR
Essigmann
John M
JM
Croy
Robert G
RG
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity*; D018736:DNA Adducts / Q000737:chemistry / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D009588:Nitrogen Mustard Compounds / Q000627:therapeutic use* / Q000633:toxicity*; D011471:Prostatic Neoplasms / Q000188:drug therapy; D021241:Spectrometry, Mass, Electrospray Ionization; D013256:Steroids / Q000627:therapeutic use* / Q000633:toxicity*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
C513485:(3-(4-(bis(2-chloroethyl)amino)phenyl)-3-propyl)carbamic acid 2-(6-(17-hydroxy-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta(a)phenanthren-11-yl)hexylamino)ethyl ester; D000970:Antineoplastic Agents; D018736:DNA Adducts; D009588:Nitrogen Mustard Compounds; D013256:Steroids