Conceptually new deltanoids (vitamin D analogs) inhibit multistage skin tumorigenesis

Development of vitamin D analogs (deltanoids) as chemopreventive agents req uires separation of desirable antiproliferative and pro-differentiating act ivities from the undesirable calcemic activity also found in the hormone ca lcitriol (1 alpha,25-dihydroxyvitamin D-3). Therefore, several conceptually new deltanoids were synthesized with modifications to the 1 alpha- and/or 25-hydroxyl groups, positions traditionally considered essential for stimul ating biological responses, In this study, 1 beta-hydroxymethyl-3-epi-25-hy droxyvitamin D-3, a non-calcemic CH2 homolog of the natural hormone with an tiproliferative activity in vitro, was ineffective as an inhibitor of 12-O- tetradecanoylphorbol-13-acetate (TPA)-induced induction of ornithine decarb oxylase activity in mouse epidermis. However, a hybrid analog incorporating not only the calcemia-ablating 1 beta-hydroxymethyl alteration, but potent iating C,D ring 16-unsaturation and side chain 24,24-fluorination and 26,27 -homologation was found to be as effective as calcitriol, Several non-calce nlic 24- or 25-t-butyl sulfones, some containing side chain fluorination bu t all lacking the 25-hydroxyl group, were also shown to be active in this a ssay. Three sulfones and the 1 beta-hydroxymethyl hybrid were evaluated as inhibitors of multistage carcinogenesis in mouse skin, Female CD-1 mice wer e initiated with a single dose of 7,12-dimethylbenz[a]anthracene acid then promoted twice weekly for 20 weeks with TPA, Deltanoids were applied topica lly 30 min before TPA, Unlike calcitriol, none of the atypical deltanoids a ffected body weight gain in these animals. Minimal effects on urinary calci um excretion were observed following chronic treatment with these analogs. All deltanoids inhibited the incidence and multiplicity of papilloma format ion, with the hybrid analog showing the greatest efficacy. With this deltan oid, tumor incidence was significantly reduced by 28% and tumor multiplicit y by 63%. These results, coupled with the rich chemical diversity available in side chain sulfur-containing deltanoids, particularly when combined wit h A ring modifications such as 1 beta-hydroxylalkyl groups, provide importa nt new advances in the fundamental understanding of chemical structure-biol ogical activity relationships as well as more potent and safe vitamin D ana logs for cancer chemoprevention and other medicinal uses.