CHEMOPREVENTION BY DEHYDROEPIANDROSTERONE AND INDOMETHACIN IN A RAT MULTIORGAN CARCINOGENESIS MODEL

The chemopreventive efficacy of dehydroepiandrosterone (DHEA) and indo methacin (IM) alone or in combination was investigated in a rat multio rgan carcinogenesis model. These two chemicals mere selected as chemop reventive agents with different functions. Animals mere sequentially g iven five carcinogens with different organ target sites in the first 4 -week initiation period. One week after its completion, the rats recei ved 0.3% DHEA in the diet, 20 ppm IM in the drinking water, or 0.3% DH EA + 20 ppm IM until experimental week 28. DHEA enhanced hepatocarcino genesis, but concurrent treatment with IM suppressed tumor development as compared to the DHEA group, DHEA inhibited tumor development in th e thyroid, with a similar tendency observed for the small intestine. I n addition, treatment with this hormone decreased occurrences of prene oplasias in the urinary bladder and seminal vesicles. Treatment with I M clearly suppressed development of preneoplasias or neoplasias in the lung and small and large intestines. In the urinary bladder, treatmen t with IM tended to decrease preneoplastic lesion development. Analysi s of multiplicity of total tumors of any category revealed comparable values for DHEA and control groups, while the IM group showed a signif icant reduction. IM in combination with DHEA caused suppression as com pared to DHEA alone. In a separate 8-week experiment, DHEA or IM were administered for 4 weeks after prior carcinogen application, and bioch emical responses in the target organs were investigated. DHEA increase d glucose-6-phosphate dehydrogenase levels in the liver but caused a d ecrease in the small intestine. In addition, DHEA decreased serum T4 b ut not T3. IM decreased prostaglandin E(2) content in the small intest ine. In conclusion, although DHEA or IM exert significant chemoprevent ive effects in multiorgans with the exception of the DHEA-treated live r case, treatment in combination did not result in amplification of th eir beneficial influence. Our results suggest the possible application of IM for chemoprevention in high-risk individuals, but the question of effects of DHEA in the liver must be answered before this hormone c an be considered for use in humans.