Abstract
The acyclic nucleoside phosphonate analogue cidofovir is a broad-spectrum anti-DNA virus agent, which also possesses potent inhibitory activity against various tumors associated with papillomaviruses in animal models and patients. Moreover, we recently described the potent inhibition of polyomavirus (PyV)-induced hemangioma formation in rats by cidofovir. This activity could not be explained by an antiviral mechanism. We have now evaluated the effect of cidofovir on the growth of hemangiosarcomas originating from PyV-transformed (PV/2b/35) cells, which do not produce polyomavirus. In vitro, cidofovir proved to be cytostatic for PV/2b/35 cells at a 50% cytostatic concentration (CC(50)) of 2.3 microg/ml. At cidofovir concentrations > or =20 microg/ml, cytotoxicity due to induction of apoptosis was observed. In vivo, intratumoral therapy with cidofovir, at 100 mg/kg 3 times a week, completely inhibited the development and even caused regression of established PV/2b/35 hemangiosarcomas in nude mice. Five days after the start of treatment, few proliferating cells were noted in the cidofovir-treated tumors, whereas control tumors were characterized by high expression of proliferating cell nuclear antigen (PCNA). Moreover, cidofovir induced apoptosis in the hemangiosarcomas, as evidenced by Tunel (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) staining. Also after intraperitoneal administration, cidofovir afforded a prominent protection against the growth of intraperitoneally or intracerebrally inoculated hemangiosarcoma cells in SCID mice. In conclusion, cidofovir possesses a direct antitumor activity, which is mediated by induction of tumor cell apoptosis. Cidofovir should be further explored for its potential in the treatment of fast-growing vascular tumors, like hemangiomas and hemangiosarcomas.
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