Worm Breeder's Gazette 5(2): 52
These abstracts should not be cited in bibliographies. Material contained herein should be treated as personal communication and should be cited as such only with the consent of the author.
Chemical carcinogenesis is thought to proceed in two stages: initiation and promotion. Tumor promoters are agents that, although not themselves carcinogenic, induce tumors in animals previously exposed to a carcinogen (initiator). Phorbol esters are the most potent known tumor promoters. We have been studying how phorbol esters act as tumor promoters, taking advantage of C. elegans, a favorable system for genetic and developmental studies. The animal was treated with the tumor promoting phorbol esters TPA ( 12-0-tetradecanoyl-phorbol-13-acetate) and PDD (phorbol 12,13- didecanoate). Both TPA and PDD at concentrations as low as 10-7M arrested growth when young animals were treated, reduced brood size when adults were treated, and caused uncoordinated movement in treated animals of any developmental stage. Conversely, the nonpromoting derivatives phorbol and 4alpha-PDD (4alpha-phorbol 12,13-didecanoate) used as controls showed no effects on the animal. The same pattern of structure-activity relationship has been observed in many biological and biochemical studies (cf. Delcos et al. 1980). The low concentrations of the compounds required to produce the effects and the characteristic structure-activity relationship observed suggest that the effects are specific and can be subjected to rigorous genetic and developmental analysis. We have isolated many mutants resistent to tumor promoters. The genetic characterization of mutants resistent to TPA suggests that no more than a few genes are involved in TPA action on the animal. Also, all of the TPA resistent mutants so far tested are resistent to PDD and at least one of the tumor promoters that are not phorbol derivatives. The approach we are taking we hope will lead to the eventual understanding of how tumor promoters act in chemical carcinogenesis.