bryostatin-1 and phorbol-12-13-didecanoate

Phorbol esters and related compounds provide a promising source of potential anticancer agents. The mechanism of their toxicity, however, is unclear, and interpretation has been complicated by the conflicting responses exhibited by different transformed cell lines. Previously we showed that in primary thyroid follicular cells, expression of mutant p21ras conferred a striking sensitivity to the toxic effects of phorbol esters. We have now extended this work using a thyroid cell line with an inducible mutant ras gene to exclude the possibility that this result was a trivial consequence of the marked growth stimulation induced in these cells by mutant p21ras. Furthermore, by assessing the action of a panel of phorbol esters and a potential chemotherapeutic agent, bryostatin, we demonstrated that this phenomenon was only a function of biologically active phorbol esters. These results provide a molecular rationale for the development of phorbol ester analogues as chemotherapeutic agents.

Topics: Antineoplastic Agents; Bryostatins; Cell Division; Cell Line; DNA; Epithelial Cells; Epithelium; Gene Expression Regulation; Genes, ras; Humans; Lactones; Macrolides; Models, Biological; Mutation; Phorbol 12,13-Dibutyrate; Phorbol Esters; Proto-Oncogene Proteins p21(ras); Structure-Activity Relationship; Tetradecanoylphorbol Acetate; Thyroid Gland; Zinc