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Quantitative Correlation between in Vitro and in Vivo Activities of Phorbol Esters¹

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

The potent mouse skin tumor promoter phorbol 12-myristate 13-acetate (PMA) has been previously shown to stimulate increased deoxyglucose transport and to cause loss of the large external transformation-sensitive glycoprotein (LETSP) from the surface of normal chicken embryo fibroblasts. We have now obtained dose-response data for loss of LETSP in chicken embryo fibroblasts induced by six other phorbol esters. With one exception, these derivatives all caused a comparable maximal decrease in LETSP, whereas their half-maximally effective doses (ED₅₀'s) varied over a range of four orders of magnitude. Good quantitative correlation was obtained between these ED₅₀'s in the chicken embryo fibroblast system and the known inflammatory potencies (quantity causing ear inflammation in 50% of a group of treated mice, ID₅₀'s) of these derivatives in the mouse ear assay. With respect to stimulation of deoxyglucose transport, the phorbol esters examined fell into two categories. PMA, phorbol 12,13-diacetate, and phorbol 12,13,20-triacetate showed ED₅₀'s for stimulating deoxyglucose transport which closely matched their ED₅₀'s for causing loss of LETSP and which thus also correlated well with the quantity causing ear inflammation in 50% of a group of treated mice, ID₅₀'s, in the mouse ear assay. Others, phorbol 12,13-didecanoate, phorbol 12,13-dibenzoate, and 4-O-methylphorbol 12-myristate 13-acetate, were 4- to 9-fold more potent in stimulating deoxyglucose transport than in causing LETSP loss. Unlike the phorbol esters, the parent diterpene phorbol and free myristic acid had little effect on deoxyglucose transport or LETSP levels at concentrations up to 3 mM (phorbol) or 0.2 mM (myristic acid), above which toxicity was observed. For PMA, the relation between stimulation of deoxyglucose transport and toxicity was examined. In contrast to an ED₅₀ for stimulation by PMA of 3.7 nM, inhibition of this stimulation occurred only with an ED₅₀ of 3.3 µM.

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

² Predoctoral Fellow of the Pharmaceutical Manufacturers Association.

³ To whom requests for reprints should be addressed.

Received 9/11/78. Accepted 11/14/78.

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