Phorbol Esters, Fatty Acids and Tumour Promotion

Abstract

CROTON oil is a complex lipid mixture obtained from the seeds of Croton tiglium L. (family Euphorbiaceae), a leafy shrub native to India and Ceylon. This oil has been used medicinally for its counterirritant, vesicant, and cathartic properties (a practice long since abandoned for humans). It is also a potent promoter of tumour formation in mouse skin¹. The active principles of croton oil have been isolated and identified as diesters of the diterpene alcohol phorbol, of which 12-O-tetradecanoylphorbol-13-acetate (TPA) is the most active biologically^2,3. TPA induces changes in cellular morphology⁴, stimulates cell division^5,6, and is the most powerful tumour promoter known^2,3,7. The extremely low doses needed to elicit these responses (10⁻⁸–10⁻⁶ M in vitro and 17 × 10⁻⁹ mol per application in vivo), plus the fact that minor structural changes in TPA eliminate its activity^2,6, indicate that the interaction with the target cells is structurally specific and TPA is therefore a valuable tool for examining not only the control of DNA synthesis and cell division, but also those events controlling tumour formation.