This proposal has two major objectives. The first is to find effective inhibitors of carcinogen-induced neoplasia of the large bowel. There are two components to this objective, one relating to direct acting carcinogens and the other to carcinogens requiring activation. A proposed strategy for inhibiting direct acting carcinogens occuring within the lumen of the large bowel is by use of high molecular weight inhibitors which are not absorbed or are poorly absorbed from the gastrointestinal tract. Two such groups of inhibitors are to be investigated. One are bis-di-tert-butyl phenol substituted mellitenes, and the other are compounds containing multiple phenolic functions on a mesitylene or benzene ring. Studies of the effects of the test compounds on neoplasia of the large bowel from N-methyl-N-nitrosourea administered intrarectally to rodents will be used as an initial experimental model. Work on inhibition of carcinogens activated in tissues will focus initially on the large bowel carcinogen methylazoxymethanol (MAM). The neoplastic effects of MAM are inhibited by butylated hydroxyanisole (BHA). Studies of compounds related to BHA are proposed to determine the relationship between chemical structure and inhibitory activity. Pertinent to this endeavor will be a determination of their effects on NAD ion-dependent alcohol dehydrogenase, a putative activating system for MAM. The second major objective of the present proposal is to identify compounds currently in the environment that have the capacity to inhibit large bowel carcinogens. Major emphasis will be placed on naturally-occurring phenols and coumarins.
NIH ExPorter
NIH ExPorter