Chemopreventive activity of a C-glucuronide analog of N-(4-hydroxyphenyl) retinamide-O-glucuronide against mammary tumor development and growth

The long term chemopreventive effects of the N-(4-hydroxyphenyl) retinamide -O-glucuronide (4-HPROG), and its stable C-linked benzyl glucuronide analo g retinamidobenzyl glucuronide (4-HPRCG) on the growth and development of 7 ,12-dimethylbenz[a]anthracene-induced mammary tumors were compared. The ret inamidobenzyl glucuronide is stable toward acid hydrolysis and resists the actions of beta-glucuronidase. The results indicate that the C-linked glucu ronide analog 4-HPRCG has a greater chemopreventive potency than an equimol ar concentration of 4-HPROG. Tumor latency was 15% longer in rats fed 2 mmo l/kg diet of 4-HPRCG as compared to 4-HPROG. At 80 days post DMBA-intubatio n, tumor incidence was 57% and 27% in the 4-HPROG and 4-HPRCG treated mts, respectively Tumor multiplicity was also markedly decreased in the 4-HPRCG treated rats. At 80 days post DMBA intubation the control rats had an avera ge of 1.43 tumors/rat compared to 0.71 and 0.36 tumors/rat in the 4-HPROG a nd 4-HPRCG respectively. The higher potency and low toxicity of 4-HPRCG sug gest that this stable analog may have an in vivo chemopreventive advantage over its analog, 4-HPROG. The results also demonstrated that these glucuron ide analogs do not bind effectively in vitro either to the nuclear retinoid receptors or to the cellular retinoid binding proteins. Regardless of the mode of action of these retinoids, they are clearly effective chemopreventi ve agents.