Abstract
Several natural and synthetic retinoids (vitamin-A derived analogies) were examined for their potential anti-cancer activity in both in vivo animal models and a novel in vitro human keratinocyte clonal growth bioassay system. The natural retinoids included all-trans-retinoic (RA), 13-cis-retinoic acid, 4-oxoretinoic acid, and retinol. Among the synthetic retinoids tested were all trans N-(4-hydroxy(phenyl)retinamide, 3-substituted oxoretinoic acids, and 13 cis-N-ethylretinamide. The animal models employed were: 1) vitamin A-deficient hamster tracheal organ assay (HTOC); 2) the benzo(α)pyrene-induced squamous metaplasia in a hamster tracheal organ system (BP-HTOC); 3) the mouse skin tumor promoter (TPA)-induced ornithine decarboxylase enzyme assay(ODC); 4) the mouse skin papilloma (MPA) assay; and 5) a novel retinoid bioassay in which retinoids display IC50 values to inhibit clonal growth of NHK. All-trans-RA, 4-oxoretinoic acid and retinol were consistently more active than any of the synthetic derivatives in all bioassays tested. A statistical model was developed and significant positive correlations were found between: 1) ED50 values in the HTOC system and reduction in TPA-induced ODC enzyme activity; 2) tumors per animal in the MPA bioassay and suppression of TPA-induced ODC activity; and 3) a positive correlation between suppression of tumors per animal in the MPA assay, and retinoid inhibition of keratinocyte clonal growth. Test retinoids, were tested for their capacity to inhibit the clonal growth of a squamous carcinoma cell line (SCC-25), which were found to be 2 - 3 logs less sensitive for each tested retinoid than the corresponding activity against NHK cells. Antineoplastic retinoid drugs were reviewed.
Highlights
Carcinogenesis is a multistep process that alters normal phenotype of cells into malignant counterparts, which acquire the ability to invade and metastasize, resulting in clinically frank cancers
Test retinoids, were tested for their capacity to inhibit the clonal growth of a squamous carcinoma cell line (SCC-25), which were found to be 2 - 3 logs less sensitive for each tested retinoid than the corresponding activity against normal human keratinocytes (NHK) cells
We reported results showing that retinoids were active in reversing keratinization in the standard vitamin A-deficient hamster tracheal organ culture (HTOC) correlated with the biological activity of retinoids active in reversing keratinization in the
Summary
Carcinogenesis is a multistep process that alters normal phenotype of cells into malignant counterparts, which acquire the ability to invade and metastasize, resulting in clinically frank cancers. The development of new retinoids has been based primarily on existing data that indicate that substituent modifications could be made at either the nonpolar cyclohexanol ring or at the opposite free carbonyl terminus or at both ends of the vitamin A molecule [13] Many of these have been found to have potential cancer chemopreventive activity [14] [15]. It was reported that the bifunctional retinoids are ineffective as they do not have any binding affinity to the cytoplasmic retinoid receptor CRBPs; the class of retinoyl-amino acids has been reported to possess activity in the hamster tracheal organ culture (HTOC) bioassay [15] [16] Close examination of these data, indicates that retinoyl-amino acids have anywhere from 3 - 5 logs less activity than t-RA. We report the development of a novel bioassay that employs a rapid and effective in vitro keratinocyte clonal growth method to yield a sensitive rank order of the retinoid potencies with both the ODC and the MPA bioassays
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