Antiproliferative effects of acyclic nucleoside phosphonates on human papillomavirus (HPV)-harboring cell lines...

Acyclic nucleoside phosphonates (ANPs) possess a broad-spectrum activity against DNA viruses and retroviruses. HPMPC (cidofovir) has proved to be effective in the treatment of HPV-associated diseases. We have evaluated the effects of various ANPs [i.e., 3-hydroxy-2-phosphonylmethoxypropyl derivatives of adenine (HPMPA) and cytosine (HPMPC, cidofovir)]; cyclic HPMPC (cHPMPC); 9-(2-phosphonylmethoxyethyl) derivatives of adenine (PMEA, adefovir), guanine (PMEG), and 2,6-diaminopurine (PMEDAP); and cyclo-propyl PMEDAP (cPr-PMEDAP), several other antiviral drugs [i.e., acyclovir (ACV), ganciclovir (GCV), foscarnet (PFA), and ribavirin]; the antitumor agents cytarabine (AraC) and 5-fluorouracil (5-FU); and the immunosuppressant mycophenolic acid (MPA) on the proliferation of human cervical keratinocytes immortalized by HPV-33 (CK-1 cells) and the cervical carcinoma cell lines containing HPV-16 (CaSki and SiHa) or HPV-18 (HeLa). In vitro incubation of these cell lines with ANPs resulted in a concentration- and time-dependent inhibition of cell proliferation. This inhibitory effect was most striking for HPMPC. The 50% inhibitory concentration (IC50) of HPMPC decreased from 20-50 microg/ml at day 3 to 0.6-2 microg/ml at day 7. When the IC50 values of the ANPs for the various HPV-harboring cells were compared with those for primary human keratinocytes isolated from normal cervix, HPMPC emerged as the most selective ANP, with a selectivity index (SI) in the range of 15-42. When IC50 values as a function of time were determined for several tumor cell lines (i.e., human melanomas, lung, colon, and breast carcinomas), ANPs again showed an antiproliferative effect as a function of time, although of a lower extent (5- to 25-fold decrease in the IC50 values between days 3 and 7) than for the HPV-positive cells. Treatment of SV40- and adenovirus-transformed cells with ANPs resulted in the inhibition of cell proliferation as a function of time, similar to that observed with HPV-positive cells, HPMPC and cHPMPC being the most potent antiproliferative agents. These results suggest that the antiproliferative activity of ANPs, in particular HPMPC, against HPV-bearing tumor cells may be explained, at least in part, by a specific inhibitory effect on rapidly proliferating cells, and the presence of the HPV genome might enhance the sensitivity of cells to HPMPC due to interactions of the viral-transforming proteins with products of the tumor suppressor genes.