Potent inhibition of hemangiosarcoma development in mice by cidofovir

The acyclic nucleoside phosphonate analogue cidofovir is a broad-spectrum a nti-DNA virus agent, which also possesses potent inhibitory activity agains t various tumors associated with papillomaviruses in animal models and pati ents. Moreover, we recently described the potent inhibition of polyomavirus (PyV)-induced hemangioma formation in rats by cidofovir. This activity cou ld not be explained by an antiviral mechanism. We have now evaluated the ef fect of cidofovir on the growth of hemangiosarcomas originating from PyV-tr ansformed (PV/2b/35) cells, which do not produce polyomavirus. In vitro, ci dofovir proved to be cytostatic for PV/2b/35 cells at a 50% cytostatic conc entration (CC50) of 2.3 mug/ml. At cidofovir concentrations greater than or equal to 20 mug/ml, cytotoxicity due to induction of apoptosis was observe d. In vivo, intratumoral therapy with cidofovir, at 100 mg/kg 3 times a wee k, completely inhibited the development and even caused regression of estab lished PV/2b/35 hemangiosarcomas in nude mice. Five days after the start of treatment, few proliferating cells were noted in the cidofovir-treated tum ors, whereas control tumors were characterized by high expression of prolif erating cell nuclear antigen (PCNA). Moreover, cidofovir induced apoptosis in the hemangiosarcomas, as evidenced by Tunel (terminal deoxynucleotidyl t ransferase-mediated dUTP nick end labeling) staining. Also after intraperit oneal 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 a ctivity, which is mediated by induction of tumor cell apoptosis. Cidofovir should be further explored for its potential in the treatment of fast-growi ng vascular tumors, like hemangiomas and heman-giosarcomas. (C) 2001 Wiley- Liss, Inc.