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Ribonucleotide reductase inhibitors enhance cidofovir‐induced apoptosis in EBV‐positive nasopharyngeal carcinoma xenografts
Author(s) -
Wakisaka Naohiro,
Yoshizaki Tomokazu,
RaabTraub Nancy,
Pagano Joseph S.
Publication year - 2005
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21096
Subject(s) - cidofovir , ribonucleotide reductase , nasopharyngeal carcinoma , biology , apoptosis , cancer research , virology , nucleoside , virus , cell growth , cell culture , microbiology and biotechnology , biochemistry , medicine , genetics , protein subunit , gene , radiation therapy
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. © 2005 Wiley‐Liss, Inc.