Chemopreventive activities of C-glucuronide/glycoside analogs of retinoid-O-glucuronides against breast cancer development and growth.
The O-glucuronide analog of N-(4-hydroxyphenyl)retinamide (4-HPROG) has shown a greater chemopreventive activity than the parent N-(4-hydroxyphenyl)retinamide (4-HPR). However, this compound is relatively unstable. In order to improve stability and efficacy, we have prepared a number of stable C-linked analogs of 4-HPROG (C-phenyl and C-benzyl glucuronosyl, glucosyl, and xylosyl analogs). These analogs are stable toward acid hydrolysis and the glucuronosyl analogs resist the actions of beta-glucuronidase. The analogs were prescreened for their antiproliferative potential in vitro using cultured human MCF-7 breast cancer cells. Selected analogs were then evaluated for their ability to inhibit the development and growth of tumors in the 7,12-dimethylbenzanthracene-induced rat mammary tumor model. Although the stable C-linked analogs bound poorly to the nuclear retinoic acid receptors, many showed more potency than the less stable 4-HPROG in inhibiting tumor incidence and multiplicity in vivo. The glucuronide/glucoside analogs are more potent than the xylosides, and the C-benzyl more effective than the C-phenyl analogs. The higher potency of at least two C-linked analogs (retinamidobenzyl glucuronide and retinamidobenzyl glucose) suggests that these analogs may have a chemopreventive advantage over the parent retinamide and its natural O-glucuronide.
Curley
R W
RW
Department of Surgery, Ohio State University, Columbus 43210, USA.
Abou-Issa
H
H
Panigot
M J
MJ
Repa
J J
JJ
Clagett-Dame
M
M
Alshafie
G
G
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy; D004354:Drug Screening Assays, Antitumor; D005260:Female; D017313:Fenretinide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D005965:Glucuronates / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured
D016588:Anticarcinogenic Agents; D005965:Glucuronates; C084238:N-((4-hydroxyphenyl)retinamide)-O-glucuronide; D017313:Fenretinide; D015127:9,10-Dimethyl-1,2-benzanthracene