It is becoming apparent that the differential susceptibility of animal species and strains to chemical carcinogenesis may be determined by critical events not only at the stage of initiation, but also at the stage of promotion. Similar considerations probably apply to mechanisms determining the organospecificity of chemical carcinogens. We assume that, in some cases, the target organs of susceptible species and strains, in contrast to nonsusceptible species and strains, may be in a state of """"""""constitutive promotion"""""""". This state would be characterized by a permanency in a set of biochemical features which, under other circumstances, are induced by chemical promoters. In this program, we will take advantage of the differential susceptibility, to methylazoxymethanol, of certain organs of the F344 rat, the strain-2 guinea pig and of alcohol dehydrogenase positive and negative strains of Peromyscus maniculatus, to identify the metabolic pathways of the carcinogen, and to determine whether the """"""""constitutive promotional state"""""""" is correlated with deficiencies in biochemical defenses against free radical-mediated cellular damage. Since the tissues of human populations, like those of experimental animals, are at varying risks for the induction of cancer, this program addresses questions of fundamental importance in chemical carcinogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA031012-05
Application #
3169438
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1981-09-01
Project End
1987-12-31
Budget Start
1986-01-01
Budget End
1986-12-31
Support Year
5
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Naylor Dana Institute for Disease Prev
Department
Type
DUNS #
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Fiala, E S; Joseph, C; Sohn, O S et al. (1991) Mechanism of benzylselenocyanate inhibition of azoxymethane-induced colon carcinogenesis in F344 rats. Cancer Res 51:2826-30
Sohn, O S; Ishizaki, H; Yang, C S et al. (1991) Metabolism of azoxymethane, methylazoxymethanol and N-nitrosodimethylamine by cytochrome P450IIE1. Carcinogenesis 12:127-31
Hamilton, S R; Sohn, O S; Fiala, E S (1988) Inhibition by dietary ethanol of experimental colonic carcinogenesis induced by high-dose azoxymethane in F344 rats. Cancer Res 48:3313-8
Hamilton, S R; Sohn, O S; Fiala, E S (1987) Effects of timing and quantity of chronic dietary ethanol consumption on azoxymethane-induced colonic carcinogenesis and azoxymethane metabolism in Fischer 344 rats. Cancer Res 47:4305-11
Fiala, E S; Sohn, O S; Puz, C et al. (1987) Differential effects of 4-iodopyrazole and 3-methylpyrazole on the metabolic activation of methylazoxymethanol to a DNA methylating species by rat liver and rat colon mucosa in vivo. J Cancer Res Clin Oncol 113:145-50
Sohn, O S; Fiala, E S; Puz, C et al. (1987) Enhancement of rat liver microsomal metabolism of azoxymethane to methylazoxymethanol by chronic ethanol administration: similarity to the microsomal metabolism of N-nitrosodimethylamine. Cancer Res 47:3123-9
Fiala, E S; Sohn, O S; Hamilton, S R (1987) Effects of chronic dietary ethanol on in vivo and in vitro metabolism of methylazoxymethanol and on methylazoxymethanol-induced DNA methylation in rat colon and liver. Cancer Res 47:5939-43
Sohn, O S; Puz, C; Caswell, N et al. (1985) Differential susceptibility of rat and guinea pig colon mucosa DNA to methylation by methylazoxymethyl acetate in vivo. Cancer Lett 29:293-300