Selective inhibition of human papillomavirus-induced cell proliferation by(S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine

(S)-1-[3-Hydroxy-2-(phosphonylmethoxy)propyl]cytosine (HPMPC) is a nucleosi de phosphonate analog which in its active diphosphorylated form is known to inhibit herpesvirus DNA polymerase, In this study, we have demonstrated th at, in a dose-dependent manner, this compound irreversibly suppressed proli feration of cells infected with human papillomavirus (HPV), which does not possess a viral DNA polymerase, To elucidate the mechanism of cell growth i nhibition, cell cycle indicator-regulator expression, thymidine incorporati on, transcript levels of apoptosis factors, and anabolic products of HPMPC following drug treatment were evaluated, HPMPC treatment reduced WAF1 (p21) levels independent of those of p53, while proliferating cell nuclear antig en increased. However, in comparison to controls, HPMPC-treated cells displ ayed a decrease in thymidine incorporation, indicating an inhibition of hos t DNA polymerase activity, In normal primary keratinocytes, HPMPC predomina ntly accumulated in the form of the choline adduct HPMPCp-choline. However, in HPV type 16-transformed keratinocytes, HPMPCpp was the most abundant an abolic product, with little HPMPCp-choline having formed, The data imply th at an unrecognized viral factor is modulating the conversion of nucleotides , including HPMPC, to the triphosphorylated form.