Chemotherapeutic evaluation of 4-hydroxybenzylretinone (4-HBR), a nonhydrolyzable C-linked analog of N-(4-hydroxyphenyl) retinamide (4-HPR) against mammary carcinogenesis.
The antitumor effects of N-(4-hydroxyphenyl)retinamide (4-HPR), and its stable C-linked analog, 4-hydroxybenzylretinone (4-HBR) on the regression of established 7,12-dimethylbenz(a)anthracene(DMBA)-induced rat mammary tumors were compared. 4-HBR is a stable and nonhydroyzable derivative which cannot be converted in vivo to retinoic acid (RA). The results indicate that 4-HBR decreased mammary tumor volumes to the same extent as equimolar concentration (2 mmol/kg diet) of 4-HPR (-45% for 4-HBR vs. -42% for 4-HPR, p<0.01). Both 4-HPR and 4-HBR bind very poorly to nuclear retinoid receptors RARs and RXRs. The similarity of physicochemical properties of 4-HPR and 4-HBR as well as their equal antitumor potency suggests that 4-HPR like 4-HBR, is acting directly rather than through hydrolysis to free RA. Treatment with 4-HPR caused an almost 65% decrease in serum retinol levels. These results suggest that 4-HBR may have a significant chemotherapeutic advantage over 4-HPR, as the nonhydrolyzable analog may not cause night blindness which occurs as a significant side effect of 4-HPR usage.
Abou-Issa
H
H
Department of Surgery, College of Medicine, The Ohio State University, Columbus 43210, USA. Abou-Issa.1@osu.edu
Curley
R W
RW
Alshafie
G A
GA
Weiss
K L
KL
Clagett-Dame
M
M
Chapman
J S
JS
Mershon
S M
SM
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D016588:Anticarcinogenic Agents / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D002273:Carcinogens; D005260:Female; D017313:Fenretinide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D014801:Vitamin A / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*
C451736:4-hydroxybenzylretinone; D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D002273:Carcinogens; D018168:Receptors, Retinoic Acid; D014801:Vitamin A; D017313:Fenretinide; D015127:9,10-Dimethyl-1,2-benzanthracene