Cidofovir [(S)-HPMPC; (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine] is an antiviral drug that has been approved for the treatment of cytomegalovirus retinitis in AIDS patients. Cidofovir also possesses potent inhibitory activity against various human papillomavirus-induced tumors in animal models and patients. In addition, cidofovir inhibits the development of murine polyomavirus-induced hemangiomas in rats by an as-yet-uncharacterized, antivirus-independent mechanism. Here we report the inhibitory effect of cidofovir on the development of virus-independent vascular tumors originated by basic fibroblast growth factor (FGF2)-overexpressing endothelial cells (FGF2-T-MAE cells). In vitro, cidofovir was cytostatic to FGF2-T-MAE cells at a 50% cytostatic concentration of 6.7 microg/ml. Cidofovir concentrations >25 microg/ml resulted in cytotoxicity because of induction of apoptosis. Cidofovir did not affect FGF2-T-MAE cell sprouting in three-dimensional fibrin gel and morphogenesis on Matrigel at noncytotoxic concentrations. In vivo, cidofovir (100 microg/egg) completely suppressed hemangioma formation on the chick chorioallantoic membrane (CAM) induced by intra-allantoic injection of FGF2-T-MAE cells, without affecting the formation of normal CAM vessels. Accordingly, cidofovir applied locally at 200 microg/disc, reduced neovascularization on the CAM by only 35%. Intratumoral or systemic administration of cidofovir caused a significant inhibition of the growth of s.c., i.p., or intracerebral FGF2-T-MAE xenografts in nude mice and severe combined immunodeficient mice. Drug-induced apoptosis was observed in FGF2-T-MAE tumors as soon as 2 days after the beginning of treatment. In conclusion, cidofovir appears to inhibit the growth of endothelium-derived tumors via induction of apoptosis without exerting a direct antiangiogenic activity.