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Structure-Activity Relationships in Chick Embryo Fibroblasts for Phorbol-related Diterpene Esters Showing Anomalous Activities in Vivo¹

Department of Pharmacology, Harvard Medical School, Boston, Massachusetts 02115

We have previously shown that the potencies of seven phorbol esters for stimulating increased transport of deoxyglucose and causing a decrease in the large external transformation-sensitive protein in chicken embryo fibroblasts (CEF) correlate closely with their published inflammatory potencies in the mouse. We have now used the CEF culture system to examine the activity of two classes of phorbol-related diterpene esters for which inflammatory activity and the ability to promote tumors in mouse skin have been shown by others not to correspond. We find that three derivatives of 12-deoxyphorbol, which are known to be highly inflammatory in the mouse ear but which possess very low promoting activity, were much less potent in CEF than predicted by their inflammatory activity. The 12-deoxyphorbol derivatives may thus have a primary biological target distinct from that of typical phorbol esters. In contrast to the 12-deoxyphorbol derivatives, the symmetrically substituted phorbol derivatives phorbol 12,13-dibutyrate, phorbol 12,13-didecanoate, and phorbol 12,13-dimyristate displayed potencies in the CEF system that corresponded to their inflammatory rather than their promoting activities in the mouse.

In our previous work with esters of phorbol, we found that each compound had similar activity (generally within 2-fold, all within 9-fold) in the 2-deoxyglucose transport and the large external transformation-sensitive protein loss assays. In contrast, we have now found that mezerein and 20-oxo-20-deoxyphorbol 12-myristate 13-acetate were respectively 46-fold and more than 75-fold less potent for inducing large external transformation-sensitive protein loss than for stimulating 2-deoxyglucose transport. The activity of mixtures of phorbol 12-myristate 13-acetate with phorbol 12,13-diacetate, with phorbol 12,13,20-triacetate, and with phorbol 13,20-diacetate was measured for stimulation of 2-deoxyglucose transport in CEF. In each case, the compounds acted as independent complete agonists.

¹ This work was supported by Grants CA18294 and CA22895 from the National Cancer Institute.

² Predoctoral Fellow of the Pharmaceutical Manufacturers Association.

³ Fellow of the Medical Foundation, Boston, Mass. To whom requests for reprints should be addressed.