SNOECK R, ANDREI G, DE CLERCQ E, WATSON J, FRIDLAND A, LEE W; Interscience Conference on Antimicrobial Agents and Chemotherapy (42nd : 2002 : San Diego, Calif.).

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2002 Sep 27-30; 42: abstract no. V-254.

Rega Institute for Medical Research, K.U. Leuven, Leuven, Belgium.

Cidofovir [HPMPC, (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, CDV] is an acyclic nucleoside phosphonate analogue that has proved efficacious in the treatment of different manifestations of HPV-induced epithelial cell proliferation. In vitro, incubation of different HPV-positive cell lines with CDV resulted in a concentration- and time-dependent inhibition of cell proliferation. We have now evaluated the effects of salicylate and amidate esters of cyclic HPMPC on the proliferation of cervical keratinocytes immortalized by HPV-33 (CK-1 cells), and several cervical carcinoma cell lines containing either integrated HPV-16 (CaSki, SiHa and EiP8), episomal HPV-16 (W12 cells) or integrated HPV-18 (HeLa and 18-11). Cyclic HPMPC (cHPMPC) can be regarded as an ?intracellular prodrug? of CDV, since inside intact cells it is rapidly converted to CDV by cCMP phosphodiesterase. Akin to HPMPC and cHPMPC, the salicylate and amidate ester prodrugs of cHPMPC afforded a concentration- and time-dependent inhibition of cell proliferation. Interestingly, the 50% inhibitory concentration (IC50) of the amidate ester prodrugs of cHPMPC was 5- to 20-fold lower than the IC50 of HPMPC and cHPMPC, while the selectivity indices (ratio of IC50 for normal primary human keratinocyes to IC50 for HPV-positive cells after 7 days of incubation) for the amidate ester prodrugs of cHPMPC were equal to or greater than that of HPMPC. The more potent effects of the amidate esters of cHPMPC, as compared to HPMPC and cHPMPC, were confirmed in the epithelial raft culture system and in cervical carcinoma (SiHa) xenografts in athymic nude mice.

Publication Types:

• Meeting Abstracts

Keywords:

• Animals
• Cell Line
• Cytosine
• Esters
• Female
• Hela Cells
• Humans
• In Vitro
• Inhibitory Concentration 50
• Keratinocytes
• Mice
• Organophosphorus Compounds
• Papillomaviridae
• Phosphonic Acids
• Prodrugs
• Salicylates
• Uterine Cervical Neoplasms
• cidofovir
• cyclic-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine

Other ID:

• GWAIDS0027481

UI: 102267105

From Meeting Abstracts