TITLE:
Cancer Chemopreventive Retinoids: Validation and Analysis of in Vivo and in Vitro Bioassay Results
AUTHORS:
John J. Wille, Jong Y. Park, Y. Fulmer Shealy
KEYWORDS:
Cancer Chemoprevention in Vivo Bioassays, in Vitro Bioassays, Retinoids
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.7 No.13,
December
16,
2016
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.