title: The broad-spectrum anti-DNA virus agent cidofovir inhibits lung metastasis of virus-independent, FGF2-driven tumors.
abstract: The FDA-approved anti-DNA virus agent cidofovir (CDV) is being evaluated in phase II/III clinical trials for the treatment of human papillomavirus (HPV)-associated tumors. However, previous observations had shown that CDV also inhibits the growth of vascular tumors induced by fibroblast growth factor-2 (FGF2)-transformed FGF2-T-MAE cells. Here, we demonstrate that CDV inhibits metastasis induced by FGF2-driven, virus-independent tumor cells. Pre-treatment of luciferase-expressing FGF2-T-MAE cells with CDV reduced single cell survival and anchorage-independent growth in vitro and lung metastasis formation upon intravenous inoculation into SCID mice. This occurred in the absence of any effect on homing of FGF2-T-MAE cells to the lungs and on the growth of subconfluent cell cultures or subcutaneous tumors in mice. Accordingly, CDV protected against lung metastasis when given systemically after tumor cell injection. Lung metastases in CDV-treated mice showed reduced Ki67 expression and increased nuclear accumulation of p53, indicating that CDV inhibits metastasis by affecting single cell survival properties. The anti-metastatic potential of CDV was confirmed on B16-F10 melanoma cells, both in zebrafish embryos and mice. These findings suggest that CDV may have therapeutic potential as an anti-metastatic agent and warrants further study to select those tumor types that are most likely to benefit from CDV therapy.
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Leuven, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: Liekens
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Leuven, Belgium.
authors.forename: Sam
authors.initials: S
authors.lastname: Noppen
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Leuven, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Gijsbers
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Leuven, Belgium.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sienaert
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ronca
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Tobia
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Presta
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D016513:Mice, SCID; D063065:Organophosphonates / Q000494:pharmacology*; D027383:Papillomaviridae / Q000187:drug effects*; D030361:Papillomavirus Infections / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish / Q000196:embryology
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D016222:Fibroblast Growth Factor 2; D003596:Cytosine; D000077404:Cidofovir
keywords: basic fibroblast growth factor; melanoma; metastasis; nucleoside phosphonate; survival