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Toxicity of phorbol esters for human epithelial cells expressing a mutant ras Oncogene
Author(s) -
Dawson Tim,
Bond Jane,
Eccles Neil,
WynfordThomas David
Publication year - 1993
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.2940080411
Subject(s) - biology , phorbol , mutant , cell culture , microbiology and biotechnology , mechanism of action , oncogene , phorbol ester , biochemistry , in vitro , cell , gene , cell cycle , protein kinase c , genetics , signal transduction
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 p21 ras 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 p21 ras . 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.