The mechanisms of lethal action of arabinosyl cytosine (araC) and arabinosyl adenine (araA)

Cohen, Seymour S.

doi:10.1002/1097-0142(197707)40:1+<509::aid-cncr2820400717>3.0.co;2-8

Cited by 51 publications

(18 citation statements)

References 37 publications

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“…Ara-C is commonly used in the treatment of leukemias. Although Ara-C is active against a variety of DNA viruses (8), activity against an RNA virus has never been reported.…”

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confidence: 83%

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1-β- d -Arabinofuranosylcytosine Inhibits Borna Disease Virus Replication and Spread

Bajramović

Syan

Brahic

et al. 2002

J Virol

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Borna disease virus (BDV) is a nonsegmented, negative-strand RNA virus that causes neurological diseases in a variety of warm-blooded animal species. There is general consensus that BDV can also infect humans, being a possible zoonosis. Although the clinical consequences of human BDV infection are still controversial, experimental BDV infection is a well-described model for human neuropsychiatric diseases. To date, there is no effective treatment against BDV. In this paper, we demonstrate that the nucleoside analog 1-␤-D-arabinofuranosylcytosine (Ara-C), a known inhibitor of DNA polymerases, inhibits BDV replication. Ara-C treatment inhibited BDV RNA and protein synthesis and prevented BDV cell-to-cell spread in vitro. Replication of other negative-strand RNA viruses such as influenza virus or measles virus was not inhibited by Ara-C, underscoring the particularity of the replication machinery of BDV. Strikingly, Ara-C treatment induced nuclear retention of viral ribonucleoparticles. These findings could not be attributed to known effects of Ara-C on the host cell, suggesting that Ara-C directly inhibits the BDV polymerase. Finally, we show that Ara-C inhibits BDV replication in vivo in the brain of infected rats, preventing persistent infection of the central nervous system as well as the development of clinical disease. These findings open the way to the development of effective antiviral therapy against BDV.

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“…Ara-C is commonly used in the treatment of leukemias. Although Ara-C is active against a variety of DNA viruses (8), activity against an RNA virus has never been reported.…”

supporting

confidence: 83%

“…Ara-C is a powerful antimitotic drug (8). To test whether this affected BDV replication, we induced total growth arrest of Vero-BV cells using conventional mitotic inhibitors (5-fluoro-2Ј-deoxyuridine and uridine).…”

Section: Discussionmentioning

confidence: 99%

1-β- d -Arabinofuranosylcytosine Inhibits Borna Disease Virus Replication and Spread

Bajramović

Syan

Brahic

et al. 2002

J Virol

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“…In view of our current study, this exonuclease activity could be much more important than that previously suggested. Besides L-OddC terminated oligonucleotide, we also examined the effectiveness of APE1 exonuclease activity against the antiviral deoxyoligonucleotides analogs L-SddC, L-Fd4C (33,34), ddC (35,36), L-ddC (37), and the anticancer analogs such as dFdC (38 -41) and araC (42,43) (Fig. 1).…”

mentioning

confidence: 99%

A Novel Action of Human Apurinic/Apyrimidinic Endonuclease

Chou

Kukhanova

Cheng

2000

Journal of Biological Chemistry

106

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␤-L-Dioxolane-cytidine (L-OddC, BCH-4556, Troxacitabine) is a novel unnatural stereochemical nucleoside analog that is under phase II clinical study for cancer treatment. This nucleoside analog could be phosphorylated and subsequently incorporated into the 3 terminus of DNA. The cytotoxicity of L-OddC was correlated with the amount of L-OddCMP in DNA, which depends on the incorporation by DNA polymerases and the removal by exonucleases. Here we reported the purification and identification of the major enzyme that could preferentially remove L-OddCMP compared with dCMP from the 3 termini of DNA in human cells. Surprisingly, this enzyme was found to be apurinic/apyrimidinic endonuclease (APE1) (1), a well characterized DNA base excision repair protein. APE1 preferred to remove L-over D-configuration nucleosides from 3 termini of DNA. The efficiency of removal of these deoxycytidine analogs were as follows:This report is the first demonstration that an exonuclease can preferentially excise L-configuration nucleoside analogs. This discovery suggests that APE1 could be critical for the activity of L-OddC or other L-nucleoside analogs and may play additional important roles in cells that were not previously known.Deoxyribonucleoside analogs are among the most effective agents for the treatment of cancer and viral diseases. Most of these compounds exert their function by inhibiting cellular or viral DNA synthesis. Since the naturally occurring nucleosides are in the ␤-D-configuration, most of the nucleoside analogs were designed in that configuration. The discovery of ␤-L-2Ј,3Ј-dideoxy-3Ј-thiocytidine (L-SddC, 3TC), 1 a stereochemically unnatural L-nucleoside analog (Fig. 1) inhibitor of HIV and hepatitis B virus replication (2-6), defined a new category for the design of nucleoside analogs. Among these, ␤-L-dioxolane-cytidine (L-OddC) (Fig. 1) is the first to show potential anticancer activity (2, 3), and clinical evaluation demonstrates its effectiveness against both leukemia and solid tumors (4 -7). For activation, most nucleoside analogs require conversion to the triphosphate metabolite by several cellular enzymes. Our previous studies have shown that L-OddC can be phosphorylated by deoxycytidine kinase to its monophosphate metabolite, which is further phosphorylated by cellular kinases to its di-and triphosphate metabolites (2, 3). The latter form of L-OddC can be incorporated into DNA by DNA polymerases ␣, ␤, ␦, ␥, and ⑀ in vitro (8). Since L-OddC lacks a hydroxyl group at the 3Ј-position, it causes premature termination of DNA replication once incorporated and eventually leads to cell death. This chain termination is probably the major mechanism of action of L-OddC. We have also shown previously that the cytotoxicity of this drug is directly related to the steady-state level of L-OddC in DNA (2).The steady-state level of L-OddC in DNA is not only dependent on incorporation by DNA polymerases but also on the excision by DNA repair enzymes. We have previously observed that incorporated L-OddCMP could be excised fr...

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“…1), by phosphorylation to ara-CTP, and by deamination to ara-U (see Cohen, 1977, for a review). 1), by phosphorylation to ara-CTP, and by deamination to ara-U (see Cohen, 1977, for a review).…”

Section: Introductionmentioning

confidence: 99%

New ara-C resistant mutants of the Chinese hamster ovary cells

1985

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Mutants of Chinese hamster ovary (CHO) cell resistant to cytosine arabinoside (ara-C), an inhibitor of DNA synthesis and antitumour drug, have been isolated and characterized both biochemically and genetically. Mutants occurring spontaneously and those induced by treatment with 2V r -methyl-2V y -Nitro-.A r -nitrosoguanidine (MNG), were obtained at a frequency of 0-24 x 10~6 and 3-4 x 10~6 respectively. The mutants showed a stable ara-C resistant phenotype which was inherited as a dominant trait in genetic crosses. The wild type (CHO K-1) and the mutant (103, 002 and 003) cells showed no differences in the levels of the uptake of ara-C or of its degradation. Results of biochemical studies further excluded the involvement of deaminase, kinase and ribonucleotide reductase as the possible factor(s) in conferring drug resistance to the mutant cells. However, the wild type and mutant DNA polymerases differed in the level of the in vitro incorporation of specific dNMP in the presence of ara-CTP. These data suggested that the wild-type DNA polymerase which becomes error prone in the presence of ara-CTP may cause the drug sensitivity of the wild-type cells and that a change in the mutant enzyme making it resistant (or less prone) to ara-CTP induced errors in dNMP incorporation may control the drug resistance of the mutant cells.

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The mechanisms of lethal action of arabinosyl cytosine (araC) and arabinosyl adenine (araA)

Cited by 51 publications

References 37 publications

1-β- d -Arabinofuranosylcytosine Inhibits Borna Disease Virus Replication and Spread

1-β- d -Arabinofuranosylcytosine Inhibits Borna Disease Virus Replication and Spread

A Novel Action of Human Apurinic/Apyrimidinic Endonuclease

New ara-C resistant mutants of the Chinese hamster ovary cells

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