Results of the use of vitamin A and retionoids in cutaneous malignancies

Abstract

Pharmac. Ther. Vol. 40, No. I, pp. 107-122, 1989 Printed in Great Britain. All rights reserved Copyright © 1988 Pergamon Press pie Guest Editor: R. M. MACKIE RESULTS OF THE USE OF VITAMIN A AND RETINOIDS IN CUTANEOUS MALIGNANCIES S. M. LIPPMAN and F. L. MEYSKENS, JR Department of Internal Medicine and Arizona Cancer Center, University o f Arizona, Tucson, Arizona, U.S.A. INTRODUCTION Vitamin A was identified long ago as an essential agent in the normal differentiation and maturation of epithelial tissues (Moore, 1967; Wolbach and Howe, 1925; Wolf, 1984). Laboratory research has demonstrated clearly that vitamin A deficiency enhances the effect of chemical carcinogens and tumor promoters and that replacing vitamin A reverses neoplastic abnormalities in these tissues (Lippman et aL, 1987a; Lotan, 1980; Lotan and Nicolson, 1977; Moon et al., 1983). Clinical study has documented that many preneoplastic and neoplastic disorders respond to vitamin A and its natural and synthetic derivatives (retinoids) (Lippman et aL, 1987b). This chapter will present a brief review of the data from in vitro and animal skin carcinogenesis model studies that unequivocally demonstrate the anticancer activity of retinoids and a detailed discussion of the growing data from human studies employing retinoids to treat cutaneous neoplastic and preneoplastic processes. MECHANISMS A vast amount of laboratory data has accumulated on the potent antipromoter, antiproliferative and differentiation-inducing effects of vitamin A derivatives on many malignant cell types (Lippman et al., 1987a; Lotan, 1980; Moore, 1967; Wolbach and Howe, 1925; Wolf, 1984). Despite extensive investigation, the mechanism(s) of action which causes the diverse cellular changes modulated by retinoids remains incompletely understood. Recently, however, it has become possible to hypothesize a basic mechanism underlying these other actions and to present a unifying picture of retinoid effects. This involves the protein kinase C/phosphoinositol cascade system. Phorbol esters have been identified as primary promoters of carcinogenesis. Therefore, protein kinase C (PK-C), the phorbol ester receptor, plays a critical role in the promotion phase of the carcinogenic process (Nishizuka, 1986). Recently, PK-C has been implicated in the mediation of many phorbol ester-promoted actions, such as ornithine decarboxylase induction and epidermal growth factor receptor down regulation (Jetten and Shirley, 1986). Membrane-bound (activated) PK-C may transmit signals to the nucleus to regulate gene (or oncogene) transcription by phosphorylating proteins and may act by nontranscriptional actions as well, such as by phosphorylating the EGF receptor. Recent work by Cope and others proposes the theory that retinoids modulate PK-C activity (Cope et al., 1986; Jetten and Shirley, 1986; Lockyer et al., 1984). Cope et al. (1986) have shown through their study of mouse brain PK-C that, although unbound retinoid binding proteins (Apo-cRABP and Apo-cRBP) are substrates for PK-C, the holo-forms (e.g. retinoic acid-cRABP) inhibit PK-C activity. Although the molecular details of retinoids' inhibition of the PK-C cascade are unclear, they do not appear to block phorbol ester binding to PK-C. Cope (1986) also showed that the regulation of PK-C alters phosphorylation of the retinoid binding proteins and other specific cytosolic and