SYNERGISTIC EFFECT OF RETINOIDS AND INTERFERON-ALPHA ON TUMOR-INDUCEDANGIOGENESIS - ANTI-ANGIOGENIC EFFECT ON HPV-HARBORING TUMOR-CELL LINES

Various retinoids and interferons exert anti-tumor effects both in exp erimental studies and in clinical trials. Recent reports indicate that they have a synergistic antineoplastic activity. Our study aimed to d etermine whether these synergistic anti-tumor effects are related to i nhibition of tumor-cell-induced angiogenesis. A further aim was to com pare the anti-angiogenic activity of various retinoids including 9-cis retinoic acid, a ligand for nuclear retinoic acid receptor RXR, given alone and in combination with interferon alpha-2a (IFN alpha-2a). An in vivo experimental model of cutaneous angiogenesis in the mouse was used. Angiogenesis was induced by intradermal injection of HPV16- or H PV18 DNA-harboring tumor-cell lines. All-trans retinoic acid (all-tran s RA), 13-cis retinoic acid (13-cis RA) and 9-cis retinoic acid (9-cis RA) as well as IFN alpha-2a applied to mice intraperitoneally for 5 c onsecutive days before induction of angiogenesis resulted in significa nt inhibition of angiogenesis. Combination of retinoids with IFN alpha -2a led to a synergistic inhibition of angiogenesis, as compared to th e effects of the drugs given alone. Similar results were obtained when tumor cells were preincubated in vitro with the compounds, before inj ection into untreated mice. Our findings on synergistic anti-angiogeni c effects of retinoids and IFN alpha-2a could explain, at least partia lly, the anti-tumor efficacy of combined therapy with these agents, an d provide support for the role of angiogenesis in tumor growth. (C) 19 94 Wiley-Liss, Inc.