Phorbol esters stimulate DNA synthesis and ornithine decarboxylase activity in mouse epidermal cell cultures

Abstract

TUMOUR-PROMOTING agents have been defined by their ability to promote tumour formation on carcinogen-initiated mouse skin. The most potent of these agents are the diesters of phorbol which are the active components of croton oil, the classic promoting substance. Phorbol esters can be chemically modified in a number of positions to form molecules with a wide range of promoter potency¹. Such modifications have been useful in determining structure-function relationships². A good correlation exists between the ability of phorbol esters to promote epidermal tumours and their ability to stimulate epidermal macro-molecular synthesis in vivo^3,4. In particular, all tumour promoters stimulate synthesis of epidermal DNA, although not all chemicals which induce hyperplasia are promoters¹. Recently O'Brien et al.⁵ suggested that the degree of induction of ornithine decarboxylase (ODC) activity in mouse skin after application of promoting and non-promoting compounds correlates well with their promoting potency. Evidence from our laboratory indicates that brief exposure to the potent phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA), stimulates DNA synthesis and ODC activity in mouse epidermal cell cultures (S.H.Y., T.B., E.P., D. Michael, K. Elgjo and H.H., to be published, and U.L. and S.H.Y., to be published). Using such a culture system, we have examined a series of phorbol esters to test the correlation of promoter potency in vivo with the stimulation of DNA synthesis and ODC activity in vitro.