tretinoin and nitrosobenzylmethylamine

9-cis-Retinoic acid (9-cis-RA) and N-(4-hydroxyphenyl)retinamide (4-HPR) are effective chemopreventive agents against epithelial tumors in the oral cavity, breast, and prostate. We tested the inhibitory activity of these retinoids against N-nitrosomethylbenzylamine (NMBA)-induced tumorigenesis in the rat esophagus.. Male Fischer 344 rats were randomly assigned to receive diets either lacking or containing 9-cis-RA or 4-HPR for 1 week before tumor initiation with NMBA and then for the duration of the study. NMBA metabolism, O(6)-methylguanine adduct formation, and cytochrome P450 messenger RNA (mRNA) expression in the esophagi of the rats were studied to investigate the mechanisms by which dietary 4-HPR affects tumorigenesis. All statistical tests were two-sided.. Dietary 4-HPR resulted in a dose-dependent and statistically significant enhancement (P<.05) of tumorigenesis in response to NMBA. In two different tumor bioassays, the mean tumor multiplicity for rats fed the highest concentration of dietary 4-HPR (0.8 g/kg diet) was increased by 5.9 tumors (95% confidence interval [CI] = 1.7 to 10.1 tumors) and 6.7 tumors (95% CI = 5.6 to 7.8 tumors) compared with the mean tumor multiplicity for rats that received the control diet lacking 4-HPR. Animals fed diets containing 9-cis-RA displayed no statistically significant increase in tumorigenesis. Compared with animals fed a diet lacking 4-HPR, animals fed 4-HPR had increased NMBA metabolism in esophageal explant cultures and had higher levels of O(6)-methylguanine DNA adducts and CYP2A3 mRNA in their esophagi.. Dietary 4-HPR enhances tumorigenesis in response to NMBA in the rat esophagus by increasing tumor initiation events. Dietary 4-HPR may exert paradoxical effects at some sites, such as the aerodigestive tract, by modulating the bioactivation of carcinogens in target tissues.

Topics: Alitretinoin; Animals; Antineoplastic Agents; Carcinogens; Cytochrome P-450 Enzyme System; Dimethylnitrosamine; DNA Adducts; Esophageal Neoplasms; Esophagus; Fenretinide; Male; Rats; Rats, Inbred F344; Retinoids; RNA, Messenger; Time Factors; Tretinoin

Ellagic acid (EA) and 13-cis-retinoic acid (CRA), both alone and in combination, were tested for their ability to inhibit N-nitrosobenzylmethylamine-induced tumors in the rat esophagus. Groups of male rats were fed AIN-76A diet containing EA (4 g/kg), CRA (240 mg/kg), or a combination of EA and CRA (4 g/kg and 240 mg/kg), respectively, for 25 weeks. Two weeks after initiation of the diets, NBMA (0.5 mg/kg per injection) was administered s.c. once weekly for 15 weeks. After 25 weeks on the diets, the animals were necropsied. The incidence of esophageal tumors was 97-100% in all NBMA-treated groups. The multiplicity of tumors in NBMA-treated groups was reduced significantly by EA (60%), but not by CRA, or by EA + CRA. These results demonstrate that EA and CRA do not act synergistically to inhibit NBMA-induced esophageal tumorigenesis.

Topics: Animals; Antineoplastic Agents; Body Weight; Carcinogens; Diet; Dimethylnitrosamine; Drug Synergism; Ellagic Acid; Esophageal Neoplasms; Male; Rats; Rats, Inbred F344; Tretinoin

A state of pure vitamin A deficiency, without any clinical manifestations, rapidly induces a stimulation of ornithine decarboxylase (ODC) activity and some oesophageal mucosal abnormalities (hyperkeratosis, dyskeratosis, cytonuclear abnormalities) in rats treated with N-nitrosobenzylmethylamine (NBMA). Retinol deficient rats fed with retinoïc acid (all-trans) show a mucosal ODC induction, but no morphological lesion. The association of retinoïc acid + retinol, as does retinol alone, prevents simultaneously histological lesions and enzymatic induction. In the liver of vitamin A deficient rats treated with NBMA, a stimulation of the ODC system, without any macroscopical lesions, has been observed.

Topics: Animals; Dimethylnitrosamine; Enzyme Induction; Esophageal Neoplasms; Keratosis; Neoplasms, Experimental; Ornithine Decarboxylase; Rats; Tretinoin; Vitamin A; Vitamin A Deficiency

Carcinogenic and promoting effects of RRME as isolated from the pickled vegetables in Linxian County, a high incidence area of esophageal cancer, were studied in mice and rats. RRME alone did not cause tumor in the forestomach of mice and esophagus of rats. When the mice were intubated with a single dose of nitroso-sarcosine-ethylester (NSEE), the incidence of the forestomach carcinoma was only 9.5%. However, when the mice were given gastric doses of RRME after one single dose of NSEE, the incidence was increased to 41.0%. In rats, the tumor incidence was 5.3% in nitroso-methylbenzylamine (NMBzA) group, while in NMBzA kRME group, it was 20.7%. In rats intubated with NSEE for 7 times, no carcinoma appeared in esophageal epithelium; while followed by gastric doses of RRME, the incidence of esophagus carcinoma increased up to 63.2%. The experimental results show that RRME has distinct promoting effect on the process of cocarcinogenesis initiated by NSEE and NMBzA in the forestomach of mice and esophagus of rats, but without carcinogenic effect itself. Retinamide (RI) and massive dose of vitamin C showed an obviously inhibitory effect on promoting action of RRME in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antineoplastic Agents; Ascorbic Acid; Dimethylnitrosamine; Esophageal Neoplasms; Female; Mice; Nitroso Compounds; Rats; Rats, Inbred Strains; Stomach Neoplasms; Tretinoin

Groups of Charles River Sprague-Dawley male rats were given intragastric intubations of methylbenzylnitrosamine after receiving one of the following diets for 4 weeks: control, zinc-deficient, or zinc-deficient diet plus 4% ethanol in the drinking water. One zinc-deficient group was zinc repleted after the dosing period; the other group, zinc-deficient plus 4% ethanol, received 13-cis-retinoic acid (13-cis-RA) after the dosing period. Zinc deficiency significantly enhanced esophageal tumor incidence; the addition of ethanol further enhanced tumor incidence. Zinc repletion reduced tumor incidence, whereas the addition of 13-cis-RA enhanced tumor incidence.

Topics: Animals; Body Weight; Cocarcinogenesis; Copper; Diet; Dimethylnitrosamine; Esophageal Neoplasms; Ethanol; Isotretinoin; Male; Neoplasms, Experimental; Rats; Rats, Inbred Strains; Tretinoin; Zinc

The effect of simultaneous administration of the aromatic retinoid ethyl all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoate (Ro 10-9359) on the carcinogenicity of N-nitrosomethyl benzylamine (NMBA) in the esophagus of Sprague-Dawley rats was investigated. Two doses of the retinoid, namely 30 or 60 mg/kg of diet, were tested. The retinoid induced marked toxicity including a depression of growth and pathological fractures at the high dose. In spite of the toxic effects encountered, the only statistically significant result recorded was a slight increase in the latent period of induction of the esophageal tumors. It is concluded that this study did not demonstrate any inhibitory or other effects of the retinoid on the induction of esophageal tumors by NMBA.

Topics: Animals; Carcinogens; Dimethylnitrosamine; Drug Interactions; Esophageal Neoplasms; Etretinate; Female; Male; Neoplasms, Experimental; Rats; Tretinoin