Preventing promotion of cancer that may already be initiated is an attractive approach for controlling chemical carcinogenesis in humans. However to achieve this goal mechanisms involved in promotion of cancer need to be more cleary defined. The long term objective of this proposal is to characterize tumor promotion in trout and to compare processes in the trout model with those associated with promotion in mammals. In so doing, we should be able to contribute new and useful information on some aspects of promotion still poorly understood in mammals. To achieve this goal we propose to conduct systematic tumor studies to characterize tumor promotion and to examine promoter-induced biochemical and cellular processes in trout. A sub-carcinogenic dose of aflatoxin B1 (AFB1) for embryo exposure that is promoted by subsequent dietary exposure to cyclopropene fatty acids (CPFA) and 17-Beta-estradiol (BED) will be determined in tumor studies. The dose-response promotion effect of CPFA and BED and effect of time delay between initiator and promoter stimulus will then be examined with the sub-carcinogenic dose of AFB1. Another tumor study will investigate the relationship between clastogenic potency of 4 initiators, and efficacy of 3-aminobenzamide (3-AB), an inhibitor of DNA repair, to act as a promoter. The effect of promoters on biochemical and cellular processes will be investigated by measuring effects on cell proliferation, assayed by [H3]-thymidine incorporation into nuclear DNA and ornithine decarboxylase activity; on clastogenesis, measured by DNA strand breaks by alkaline elution; and lipid peroxidation; analyzed by quantitation of diene conjugation in nuclear lipid. Carcinogen-induced clastogenesis with ethylmethane sulfonate and inhibition of its repair by 3-AB will be assessed by investigated by quantitating transfer to fluorscent labeled RTH-149 trout cells of H3-uridine from cocultured RTH-149 cells, from isolated trout hepatocytes and from isolated hepatocytes from trout prefed promoter. This approach of studying promotion of carcinogenesis in the sensitive and cost efficient trout model to provide whole animal tumor data and cellular and biochemical data should provide basic yet economical information on the mechanisms of promotion cancer that may apply to all species.
| Fong, A T; Hendricks, J D; Dashwood, R H et al. (1988) Modulation of diethylnitrosamine-induced hepatocarcinogenesis and O6-ethylguanine formation in rainbow trout by indole-3-carbinol, beta-naphthoflavone, and Aroclor 1254. Toxicol Appl Pharmacol 96:93-100 |
| Fong, A T; Hendricks, J D; Dashwood, R H et al. (1988) Formation and persistence of ethylguanines in liver DNA of rainbow trout (Salmo gairdneri) treated with diethylnitrosamine by water exposure. Food Chem Toxicol 26:699-704 |
