TOXICITY OF PHORBOL ESTERS FOR HUMAN EPITHELIAL-CELLS EXPRESSING A MUTANT RAS ONCOGENE

Phorbol esters and related compounds provide a promising source of pot ential anticancer agents. The mechanism of their toxicity, however, is unclear, and interpretation has been complicated by the conflicting r esponses exhibited by different transformed cell lines. Previously we showed that in primary thyroid follicular cells, expression of mutant p21(ras) conferred a striking sensitivity to the toxic effects of phor bol esters. We have now extended this work using a thyroid cell line w ith an inducible mutant ras gene to exclude the possibility that this result was a trivial consequence of the marked growth stimulation indu ced in these cells by mutant p21(ras). Furthermore, by assessing the a ction of a panel of phorbol esters and a potential chemotherapeutic ag ent, bryostatin, we demonstrated that this phenomenon was only a funct ion of biologically active phorbol esters. These results provide a mol ecular rationale for the development of phorbol ester analogues as che motherapeutic agents. (C) 1993 Wiley-Liss. Inc.