Cidofovir in the treatment of HPV-associated lesions

Abstract

The acyclic nucleoside phosphonate cidofovir (CDV) has proved efficacious in the treatment of different clinical manifestations of HPV-induced epithelial cell proliferation. Local intratumor injections of CDV in an immunocompetent patient with hypopharyngeal/esophageal papillomatous lesions, PCR-positive for HPV types 16 and 18, resulted in a complete regression of the tumor. Similarly, CDV, injected locally in patients with recurrent respiratory papillomatosis resulted in complete disappearance or partial remission of the lesions. Recently, a child with disseminated respiratory papillomatosis was treated with systemic (intravenous) CDV, resulting in stabilization of the disease. In addition, CDV topical gel has been successfully used for the treatment of severe, relapsing anogenital HPV lesions and cervical intraepithelial neoplasia (CIN) grade III. In vitro, treatment of HPV-positive cells (compared to normal primary human keratinocytes) with CDV has resulted in a concentration- and time-dependent inhibition of cell proliferation. Different parameters of apoptosis, i.e., (i) induction of CPP32 (caspase-3) protease activity, (ii) translocation of phosphatidylserine (PS) from the inner part of the plasma membrane to the outer layer, (iii) disintegration of the nuclear matrix protein (NMP), (iv) DNA fragmentation, (v) number of cells in apoptotic phase following cell cycle analysis, showed that the mechanism of cell death following treatment with CDV is based on apoptosis. Induction of apoptosis in HPV-positive cells by CDV was associated with accumulation of the tumor suppressor proteins p53 and pRb and the cyclin-dependent kinase inhibitor p21/WAF-1. In conclusion, CDV has great potential in the treatment of severe HPV-induced proliferative lesions, either laryngeal, esophageal/pharyngeal or genital. As CDV has proved able to induce apoptosis, in a time- and concentration-dependent manner, in a number of HPV-positive cell lines, the regression of papillomatous tumors observed with CDV in patients, may be due, at least in part, to the induction of apoptosis.