Chemical structure of cidofovir
 
 

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ABSTRACT

 
Cidofovir [(S)-HPMPC, [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine] has been approved for the treatment of cytomegalovirus (CMV) retinitis in AIDS patients and possesses potent inhibitory activity against various papillomavirus (HPV)-induced tumors in animal models and patients. In addition, cidofovir inhibits the development of murine polyomavirus (PyV)-induced hemangiomas in rats by an as yet uncharacterized antiviral-independent mechanism. 

Here we investigated the effect of cidofovir on virus-independent vascular tumors originated by basic fibroblast growth factor (FGF2)-overexpressing endothelial cells (FGF2-T-MAE cells). In vitro, cidofovir was cytostatic for FGF2-T-MAE cells with a CC50 (50% cytostatic concentration) value of 6.7 µg/ml. Concentrations higher than 25 µg/ml resulted in cytotoxicity due to induction of apoptosis. Cidofovir did not affect FGF2-T-MAE cell sprouting in 3D fibrin gel and morphogenesis on Matrigel at non-cytotoxic concentrations. 

In vivo, cidofovir (100 µg/egg) completely suppressed hemangioma formation on the chick chorio-allantoic membrane (CAM) induced by intra-allantoic injection of FGF2-T-MAE cells, without affecting the normal CAM vessels. Accordingly, cidofovir applied locally at 200 µg/disc reduced neovascularization on the CAM by 35% only. Intratumoral or systemic administration of cidofovir caused a significant inhibition of the growth of subcutaneous, intraperitoneal, or intracerebral FGF2-T-MAE-xenografts in nude and SCID 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 endothelial-derived tumors via induction of apoptosis without exerting a direct anti-angiogenic activity. Cidofovir may be explored for the treatment of tumors that are not associated with an oncogenic virus.

Cancer Res. (2001) 61: 5057-5064.