Kinetic analysis of the interaction of cidofovir diphosphate with human cytomegalovirus DNA polymerase

Xiong, Xiaofeng; Smith, Jeffrey L.; Kim, Choung; Huang, Eng‐Shang; Chen, Ming S.

doi:10.1016/0006-2952(96)00100-1

Cited by 75 publications

(43 citation statements)

References 15 publications

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“…The antiviral form of cidofovir in cells is cidofovir-PP, an analog of dCTP that inhibits viral DNA polymerases (34). To test whether viral resistance to cidofovir could be the result of reduced intracellular phosphorylation in infected cells, cells were exposed to virus and [ 3 H]cidofovir for 24 h, followed by analysis of cidofovir-PP content.…”

Section: Resultsmentioning

confidence: 99%

“…Symbols: F, placebo-treated cowpox-WT virus-infected mice; s, cidofovir-treated cowpox-WT virus-infected mice; E, placebo-treated cowpox-R (SF) virus-infected mice; ᮀ, cidofovir-treated cowpox-R (SF) virus-infected mice. (23,27) whereas cidofovir is a viral DNA polymerase inhibitor (34). Application of these data to a possible clinical situation suggests the possibility that treatment of variola or monkeypox virus infections in humans could lead to the emergence of CDV-R viruses that are cross resistant to other antiviral compounds.…”

Section: Fig 2 Treatment Of Intranasal Infections Withmentioning

confidence: 99%

“…The sensitivities of the plaquepurified WT and CDV-R poxviruses to selected antiviral compounds were determined in six-well plates of Vero 76 cells. The selected compounds represented different classes of antiviral agents, such as those inhibiting viral DNA polymerases (cidofovir, cyclic HPMPC, and HPMPA) (34), IMP dehydrogenase inhibitors (ribavirin and MPA) (11,23), and C-c 3 Ado, an inhibitor of S-adenosylhomocysteine hydrolase (10). Plates of cells were infected with about 100 PFU of virus per well, the virus was adsorbed for 1.5 to 2 h, and then twofold dilutions of antiviral compounds were applied.…”

mentioning

confidence: 99%

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Characterization of Wild-Type and Cidofovir-Resistant Strains of Camelpox, Cowpox, Monkeypox, and Vaccinia Viruses

Smee

Sidwell

Kefauver

et al. 2002

Antimicrob Agents Chemother

124

100

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Section: Resultsmentioning

confidence: 99%

Section: Fig 2 Treatment Of Intranasal Infections Withmentioning

confidence: 99%

mentioning

confidence: 99%

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Characterization of Wild-Type and Cidofovir-Resistant Strains of Camelpox, Cowpox, Monkeypox, and Vaccinia Viruses

Smee

Sidwell

Kefauver

et al. 2002

Antimicrob Agents Chemother

124

100

View full text Add to dashboard Cite

“…Cidofovir diphosphate was shown to act as a competitive inhibitor of dCTP and an alternate substrate for the HCMV DNA polymerase. Its incorporation does not directly result in chain termination (433). Like foscarnet, cidofovir diphosphate owes its selectivity to the higher affinity for viral DNA polymerases compared to cellular DNA polymerases (301).…”

Section: Cidofovirmentioning

confidence: 99%

Update on Human Herpesvirus 6 Biology, Clinical Features, and Therapy

2005

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Human herpesvirus 6 (HHV-6) is a betaherpesvirus that is closely related to human cytomegalovirus. It was discovered in 1986, and HHV-6 literature has expanded considerably in the past 10 years. We here present an up-to-date and complete overview of the recent developments concerning HHV-6 biological features, clinical associations, and therapeutic approaches. HHV-6 gene expression regulation and gene products have been systematically characterized, and the multiple interactions between HHV-6 and the host immune system have been explored. Moreover, the discovery of the cellular receptor for HHV-6, CD46, has shed a new light on HHV-6 cell tropism. Furthermore, the in vitro interactions between HHV-6 and other viruses, particularly human immunodeficiency virus, and their relevance for the in vivo situation are discussed, as well as the transactivating capacities of several HHV-6 proteins. The insight into the clinical spectrum of HHV-6 is still evolving and, apart from being recognized as a major pathogen in transplant recipients (as exemplified by the rising number of prospective clinical studies), its role in central nervous system disease has become increasingly apparent. Finally, we present an overview of therapeutic options for HHV-6 therapy (including modes of action and resistance mechanisms)

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“…1,2,25 The drug inhibits herpesvirus-encoded DNA polymerases. 27,28 The compound is a potent inhibitor of the cytolytic replication of EBV, but does not affect EBV episomal copy number or the growth of latently infected lymphocytes. 25,29 Cidofovir has a uniquely broad spectrum of indications for clinical use, encompassing DNA virus infections, as well as various experimental forms of cancer of both viral and nonviral origin, including vascular tumors, such as hemangiomas and hemangiosarcomas grown in SCID mice.…”

Section: Discussionmentioning

confidence: 99%

Ribonucleotide reductase inhibitors enhance cidofovir‐induced apoptosis in EBV‐positive nasopharyngeal carcinoma xenografts

Wakisaka

Yoshizaki

Raab‐Traub

et al. 2005

Intl Journal of Cancer

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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 EBVpositive 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 growthinhibitory 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.

show abstract

Kinetic analysis of the interaction of cidofovir diphosphate with human cytomegalovirus DNA polymerase

Cited by 75 publications

References 15 publications

Characterization of Wild-Type and Cidofovir-Resistant Strains of Camelpox, Cowpox, Monkeypox, and Vaccinia Viruses

Characterization of Wild-Type and Cidofovir-Resistant Strains of Camelpox, Cowpox, Monkeypox, and Vaccinia Viruses

Update on Human Herpesvirus 6 Biology, Clinical Features, and Therapy

Ribonucleotide reductase inhibitors enhance cidofovir‐induced apoptosis in EBV‐positive nasopharyngeal carcinoma xenografts

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