title: Ribonucleotide reductase inhibitors enhance cidofovir-induced apoptosis in EBV-positive nasopharyngeal carcinoma xenografts.
abstract: In nasopharyngeal carcinoma (NPC), Epstein-Barr virus (EBV) infection is mainly latent, and the tumor cells contain episomal viral DNA. We have shown that the acyclic nucleoside phosphonate analog, cidofovir [(S)-1-(3-hydroxy-2-(phosphonylmethoxypropyl))cytosine] (HPMPC), inhibits growth of NPC xenografts in nude mice by causing apoptosis. The ribonucleotide reductase (RR) inhibitors, hydroxyurea and didox (3,4-dihydroxybenzohydroxamic acid), have been demonstrated to inhibit neoplastic growth and are used as antiviral and anticancer agents. Here we show that RR inhibitors enhance the antitumor effect of cidofovir in EBV-transformed epithelial cells. MTT assays indicate that hydroxyurea and didox enhance cidofovir-induced cell toxicity in NPC-KT cells, an EBV-positive epithelial cell line derived from NPC. The effect is due to enhancement of apoptosis through the caspase cascade as shown by pronounced cleavage of poly(ADP-ribose) polymerase. Finally, hydroxyurea strikingly enhanced the cidofovir-induced growth-inhibitory effect on NPC grown in athymic mice. The results suggest that RR inhibitors should enhance the antitumor effect of acyclic nucleoside phosphonate analogs on NPC.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Wakisaka
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Yoshizaki
authors.forename: Nancy
authors.initials: N
authors.lastname: Raab-Traub
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Pagano
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002277:Carcinoma / Q000188:drug therapy* / Q000662:veterinary / Q000821:virology*; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020031:Epstein-Barr Virus Infections / Q000150:complications*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D006918:Hydroxyurea / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000662:veterinary / Q000821:virology*; D063065:Organophosphonates / Q000494:pharmacology*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D063065:Organophosphonates; D003596:Cytosine; D012264:Ribonucleotide Reductases; D000077404:Cidofovir; C035419:3,4-dihydroxybenzohydroxamic acid; D006918:Hydroxyurea