INHIBITION OF TUMOR CELL-INDUCED ANGIOGENESIS BY RETINOIDS, 1,25-DIHYDROXYVITAMIN-D3 AND THEIR COMBINATION

Tumor-induced angiogenesis (TIA), i.e., the ability of transformed cel ls to stimulate new blood vessel formation is an important factor cont ributing to tumor growth and invasiveness. The antiangiogenic effect o f the retinoids, all-trans retinoic acid, 13-cis retinoic and 9-cis re tinoic acid, of 1,25-dihydroxyvitamin D3, and of their combinations we re studied using an experimental system in vivo. TIA was induced in im munosuppressed mice by intradermal injection of the two human transfor med keratinocyte lines, Skv-e2, harboring DNA of human papillomavirus (HPV) type 16, and HeLa, harboring HPV18 DNA. The three retinoids and 1,25-dihydroxyvitamin D3, when administered systemically to mice, befo re the angiogenesis assay significantly decreased TIA. Their combinati on led to a synergistic inhibition of TIA. These results provide the b asis for the use of combination of retinoids and 1,25-dihydroxyvitamin D3 in treatment of neoplastic diseases.