Inhibition of mammary tumor growth by a novel nontoxic retinoid: chemotherapeutic evaluation of a C-linked analog of 4-HPR-glucuronide.

Abstract

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.

• Authors: Galal A Alshafie, Joel R Walker, Robert W Curley Jr, Margaret Clagett-Dame, Margaret A Highland, Nirca J Nieves, Laura A Stonerock, Hussein Abou-Issa
• Journal: Anticancer research (Anticancer Res) 2005 May-Jun Vol. 25 Issue 3c Pg. 2391-8 ISSN: 0250-7005 [Print] Greece
• PMID: 16082771 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Carcinogens
• Glucuronates
• N-((4-hydroxyphenyl)retinamide)-O-glucuronide
• RNA, Messenger
• Fenretinide
• Tretinoin
• 9,10-Dimethyl-1,2-benzanthracene
• Cytochrome P-450 Enzyme System
• Retinoic Acid 4-Hydroxylase

Topics

• 9,10-Dimethyl-1,2-benzanthracene
• Animals
• Antineoplastic Agents (adverse effects, pharmacology)
• Carcinogens
• Cell Growth Processes (drug effects)
• Cytochrome P-450 Enzyme System (biosynthesis, genetics)
• Female
• Fenretinide (adverse effects, analogs & derivatives, pharmacology)
• Glucuronates (adverse effects, pharmacology)
• Liver (drug effects, enzymology)
• Mammary Neoplasms, Experimental (chemically induced, drug therapy, enzymology, pathology)
• RNA, Messenger (biosynthesis, genetics)
• Rats
• Rats, Sprague-Dawley
• Retinoic Acid 4-Hydroxylase
• Tretinoin (adverse effects, pharmacology)