Putative metabolites derived from dietary combinations of calcium glucarate and N-(4-hydroxyphenyl)retinamide act synergistically to inhibit the induction of rat mammary tumors by 7,12-dimethylbenz[a]anthracene.
Calcium glucarate and N-(4-hydroxyphenyl)retinamide were evaluated individually and in combination in the diet as preventative chemical agents, by using the induction of rat mammary tumors by 7,12-dimethylbenz[a]anthracene as the test system. When tested separately over 18 weeks, optimal doses of calcium glucarate (128 mmol/kg of diet) or N-(4-hydroxyphenyl)retinamide (1.5 mmol/kg of diet) administered daily inhibited tumor incidence by 50% or 57% and tumor multiplicity by 50% or 65%, respectively. Suboptimal doses of calcium glucarate (32 mmol/kg) and of N-(4-hydroxyphenyl)retinamide (0.75 mmol/kg) inhibited tumor incidence by 15% and 5% but had no inhibitory effect on tumor multiplicity. In contrast, the combination of calcium glucarate (32 mmol/kg) and N-(4-hydroxyphenyl)retinamide (0.75 mmol/kg) inhibited tumor incidence and tumor multiplicity by 50%. Similar synergism was observed with the combination of calcium glucarate (64 mmol/kg) and N-(4-hydroxyphenyl)retinamide (0.75 mmol/kg), the inhibition being 55-60%. HPLC analysis of the bile of female rats injected intraperitoneally with a single dose of the retinamide [60 mg/kg (body weight)] showed that the excretion of the retinamide and its glucuronide were markedly suppressed by pretreatment with an oral dose of calcium glucarate [4.5 mmol/kg (body weight)].
Abou-Issa
H M
HM
Comprehensive Cancer Center, Ohio State University, Columbus 43210.
Duruibe
V A
VA
Minton
J P
JP
Larroya
S
S
Dwivedi
C
C
Webb
T E
TE
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004032:Diet; D004357:Drug Synergism; D017313:Fenretinide; D005937:Glucaric Acid / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D011919:Rats, Inbred Strains; D013400:Sugar Acids / Q000494:pharmacology*; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000494:pharmacology
D013400:Sugar Acids; D017313:Fenretinide; D014212:Tretinoin; D015127:9,10-Dimethyl-1,2-benzanthracene; D005937:Glucaric Acid