IN-VIVO INHIBITION OF ANGIOGENESIS AND INDUCTION OF APOPTOSIS BY RETINOIC ACID IN SQUAMOUS-CELL CARCINOMA

Retinoids inhibit the growth and reverse aberrant differentiation of s quamous cell carcinoma (SCC) cells in vitro. To investigate the potent ial mechanisms of antitumor activity of retinoids in vivo, we used the cervical SCC cell line ME-180 as a s.c. tumor xenograft in athymic nu de mice, After s.c. injection, tumor cells were allowed to form visibl e tumors and antitumor activity of all-trans-retinoic acid (tRA) was s tudied. tRA was administered daily for a 1-week or a 2-week period at 60 mg/kg/day. Tumor specimens were then analyzed using immunohistochem ical staining for the number of blood vessels and apoptotic cells and for proliferating cell nuclear antigen expression, Furthermore, we stu died the effect of the tRA treatment on the expression of a binding pr otein for fibroblast growth factors (BP; Gen-Bank accession no. M60047 ) that is a candidate angiogenesis modulator in SCC (F. Czubayko et al ., J. Biol. Chem., 269: 28243-28248, 1994). We found that in vivo tRA treatment reduces BP expression in SCC xenografts, inhibits their angi ogenesis, induces apoptosis of the tumor cells, and leads to a decreas e of the tumor growth rate, We speculate that the tRA down-regulation of BP is responsible for the reduction of angiogenesis.