Effects of D,L-2-Difluoromethylornithine and Indomethacin on Mammary Tumor Promotion in Rats Fed High n-3 and/or n-6 Fat Diets

Virgin female Sprague-Dawley rats (50 days of age) were administered a single intragastric 10-mg dose of 7,12-dimethylbenz(a)anthracene (DMBA). Twenty-one days later they were placed on diets containing either 20% corn oil (CO), 15% menhaden oil plus 5% corn oil (MO + COX 20% CO plus 03% w/w of the irreversible ornithine decarboxylase inhibitor, D,L-2-difluoromethylomithine (CO + DFMOX 20% CO plus 0.004% w/w of the cyclooxygenase inhibitor indomethacin (CO -+- INDO), 20% CO + 0.004% INDO -I- 03% DFMO (CO -+- INDO -+- DFMOX or 15% MO + 5% CO + 03% DFMO (MO + CO + DFMO). The incidence of DMBA-induced mammary tumors was significantly reduced in rats fed diets containing DFMO but not in rats fed the diet containing indomethacin. Incidences of mammary tumors at 16 weeks post-DMBA were 86% in rats fed the CO diet, 83% in rats ingesting the diet containing CO -+- INDO, 28% in rats fed CO -+- DFMO, 32% in rats fed diet containing CO -+- INDO + DFMO, 59% in rats fed the MO -+- CO diet, and 24% in rats fed the MO + CO + DFMO diet. The average number of tumors and tumor burden per tumor-bearing rat were reduced and tumor latency was increased in all rats fed diets containing DFMO. Body weight gain, but not food intake, of rats fed the 20% fat -I- 03% DFMO diets was significantly less than in rats fed the 20% fat diets. Prostaglandin E and leukotriene (LTB4) syntheses, ODC activity and mammary tumorigenesis were significantly inhibited by feeding the diet containing menhaden oil or by adding 03% DFMO to any of the high fat diets. Feeding a 20% CO diet containing 0.004% INDO significantly reduced prostaglandin synthesis and ODC activity and increased LTB4 synthesis of mammary tumors but did not inhibit mammary tumorigenesis. This study suggests that the 5-lipoxygenase product LTB4 may be involved in mammary tumor production. Whereas a decrease in LTB4 appears to be associated with a decrease in tumorigenesis, an increase (as seen in the indomethacin group) was not associated with any change in the tumori-genic response.