Effect of Acyclic Nucleoside Phosphonates (ANPs) on the Proliferation of Adenovirus-transformed Cell Lines as Compared to Human Papillomavirus (HPV)-harboring Cell Lines
摘要
We have shown that treatment with ANPs of cell lines harboring HPV resulted in a time-dependent inhibition of cell proliferation. This inhibitory effect is particularly more striking for cidofovir (HPMPC). A 34- to 75-fold decrease in the 50%cytotoxic concentration (CC50) at day 7 (as compared to day 3) was observed with HPMPC for several HPV-positive cell lines. A 5- to 15-fold decrease in CC50 was noted for HPMPC at day 7 in tumor cell lines non-containing HPV, but not in normal human cells. These results suggest that the anti-HPV activity of HPMPC may be explained, at least in part, by an anti-proliferative effect on rapidly proliferating cells and HPV might enhance the sensitivity of the cells to HPMPC due to an interaction of the viral transforming proteins with products of tumor suppressor genes. We have now evaluated the effects of the ANPs and other antiviral and antitumor drugs on SV40-transformed African green monkey kidney (COS-1 and COS-7) cells and adenovirus-transformed human embryo kidney (293) cells, since viral transforming proteins of these cells are also known to interact with products of tumor suppressor genes. Treatment of COS-1, COS-7 and 293 cells with ANPs resulted in inhibition of cell proliferation in function of time similar to that observed for HPV-positive cells. The CC50 of HPMPC varied from 14-22 μg/ml at day 3 to 0.55-0.88 μg/ml at day 7, while the CC50 of HPMPC for the corresponding non-transformed cells varied from 92 μg/ml (Vero cells, African green monkey kidney) and 128 μg/ml (HEL cells, human embryonic lung fibroblasts) at day 3 to 12 μg/ml (Vero cells) and 84 μg/ml (HEL cells) at day 7. These resulted in a selectivity index (ratio CC50 for non-transformed cells to CC50 for transformed cells at day 7 of 16 (COS-1 cells), 18 (COS-7 cells) and 95 (293 cells). The effect of ANPs on the interaction of viral transforming proteins with products of tumor suppressor genes is currently under investigation.