Inhibition of mammary tumor growth by a novel nontoxic retinoid: chemotherapeutic evaluation of a C-linked analog of 4-HPR-glucuronide.
Previous studies from our laboratory suggest that 4-HPROG, the O-glucuronide derivative of 4-HPR, has improved mammary cancer chemopreventive/ antitumor activities as well as reduced toxicity, as compared to 4-HPR. This O-linked glucuronide derivative is a substrate to the P-glucuronidase enzyme and may also undergo hydrolysis in vivo to the vitamin A metabolite, retinoic acid, that is toxic at high concentrations. In an effort to improve analog potency relative to its toxicity, the 4-HPROG's phenolic oxygen was replaced with a methylene group, thus preventing biological cleavage of the glucuronide moiety. The resulting C-linked analog, 4-HPR-C-glucuronide (4-HPRCG), cannot be hydrolyzed to 4-HPR. The results of this study show that 4-HPRCG is an effective chemotherapeutic agent that caused 49% regression of DMBA-induced mammary tumors in rats, while showing almost no side-effects that are often observed with other natural or synthetic retinoids, such as a reduction in blood retinol level, elevation in blood triglyceride (TG) level, and decrease in bone mineral content (BMC). These results suggest that 4-HPRCG should be considered as a better candidate for breast cancer treatment.
Alshafie
Galal A
GA
Department of Surgery and 2Division of Medicinal Chemistry, Colleges of Medicine and Pharmacy, The Ohio State University, Columbus, Ohio 43210 USA.
Walker
Joel R
JR
Curley
Robert W
RW
Clagett-Dame
Margaret
M
Highland
Margaret A
MA
Nieves
Nirca J
NJ
Stonerock
Laura A
LA
Abou-Issa
Hussein
H
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D002273:Carcinogens; D048708:Cell Growth Processes / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D017313:Fenretinide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D005965:Glucuronates / Q000009:adverse effects / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D000072516:Retinoic Acid 4-Hydroxylase; D014212:Tretinoin / Q000009:adverse effects / Q000494:pharmacology
D000970:Antineoplastic Agents; D002273:Carcinogens; D005965:Glucuronates; C084238:N-((4-hydroxyphenyl)retinamide)-O-glucuronide; D012333:RNA, Messenger; D017313:Fenretinide; D014212:Tretinoin; D015127:9,10-Dimethyl-1,2-benzanthracene; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase