A proposed mechanism of action of 1-β-d-arabinofuranosyl-cytosine as an inhibitor of the growth of leukemic cells

Chu, Ming; Fischer, Glenn A.

doi:10.1016/0006-2952(62)90225-3

Cited by 258 publications

(58 citation statements)

References 7 publications

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“…Dobersen and Greer (19) based their technique on experiments with BrdC, which is phosphorylated only in extracts of HSV-infected cells. Cooper (13) and Prusoffet al (48) 11. Effect of ara-C, ara-T, and PAA on growth ofLM cells.…”

Section: Resultsmentioning

confidence: 99%

“…Subsequently, ara-T was found to have little effect on the multiplication of tumor cells in culture (11,15) but was later shown to be somewhat inhibitory to herpesvirus replication in vivo (17,18,53,54,56). The demonstration (26) that herpes simplex virus (HSV)-infected cells contain a pyrimidine deoxyribonucleoside kinase (dPyK) with a broad substrate specificity (29,30) suggested that ara-T might be phospho- showing that ara-T at 2 x 10-M completely blocked the replication of HSV type 1 (HSV-1) and HSV type 2 (HSV-2) in BHK cells but had no measurable effect on the multiplication of uninfected BHK cells subcultured at low cell density and followed for several generations (23).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Antiviral Activity of Arabinosylthymine in Herpesviral Replication: Mechanism of Action In Vivo and In Vitro

Aswell¹,

Allen²,

Jamieson³

et al. 1977

Antimicrob Agents Chemother

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1-p-D-Arabinofuranosylthymine (ara-T), a metabolite of the sponge Tethya crypta, has shown selective activity against herpes simplex virus (HSV) replication (G. A. Gentry and J. F. Aswell, Virology 65:294-296, 1975 responsible for the selective antiviral activity of ara-T. This conclusion was further supported by experiments that showed that the replication ofa variety of dPyK-mutants of HSV-1 and HSV-2 were not affected by ara-T and that ara-T inhibited the phosphorylation of deoxycytidine and deoxythymidine by HSV-1 dPyK, but not by host deoxycytidine and deoxythymidine kinases, respectively. Ara-T also selectively inhibited the replication ofequine herpesvirus type 1 (EHV-1) in vitro and was effective against EHV-1 infection in vivo in hamsters. Further, EHV-1 was inhibited by ara-T and by bromodeoxyuridine in LM cells lacking a cytosol thymidine kinase, suggesting that EHV-1 induces a dPyK. Finally, spectrophotometric assay for thymine suggested that ara-T is not a substrate for nucleoside phosphorylase of hamster liver, and a microbiological assay indicated that substantial amounts of ara-T were excreted in the urine of uninfected hamsters that had received a single injection of 5 mg of ara-T, the amount given in each injection in the in vivo experiments with EHV-1.1-p-D-Arabinofuranosylthymine (ara-T; spongothymidine) was first isolated, rather by coincidence, by Bergmann and Feeney (5) in a study of the sterol content (4) of Tethya crypta, a sponge first described as growing almost buried in the ocean floor off the Bahamas (16). Subsequently, ara-T was found to have little effect on the multiplication of tumor cells in culture (11,15) but was later shown to be somewhat inhibitory to herpesvirus replication in vivo (17,18,53,54,56). The demonstration (26) that herpes simplex virus (HSV)-infected cells contain a pyrimidine deoxyribonucleoside kinase (dPyK) with a broad substrate specificity (29,30) suggested that ara-T might be phospho- showing that ara-T at 2 x 10-M completely blocked the replication of HSV type 1 (HSV-1) and HSV type 2 (HSV-2) in BHK cells but had no measurable effect on the multiplication of uninfected BHK cells subcultured at low cell density and followed for several generations (23). It has subsequently been shown that several other deoythymidine (dT) analogs have similar selectivity against HSV, including 5'-amino-2',5'-dideoxy-5-iodouridine, 5-ethyldeoxyuridine, 5-propyldeoxyuridine, 5-allyldeoxyuridine (8, 10); 5-bromodeoxycytidine, 5-iododeoxycytidine (13,20, 24,31); and 5-methoxymethyldeoxyuridine (2,3). This suggests that the HSV-specified dPyK may be a useful tool in

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Antiviral Activity of Arabinosylthymine in Herpesviral Replication: Mechanism of Action In Vivo and In Vitro

Aswell¹,

Allen²,

Jamieson³

et al. 1977

Antimicrob Agents Chemother

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“…It was covered in work by Pizer and Cohen 38 on its metabolism and on the potential mechanism as an antileukemic agent in the report by Chu and Fischer. 39 Since those early days, a multiplicity of agents have been approved world-wide for agents against viral diseases, in particular anti-human immunodeficiency virus (HIV), and antitumor agents. These have involved substitutions in all parts of the molecules, both the base and the sugar.…”

Section: Drugs Derived From Nucleosidesmentioning

confidence: 99%

Natural Product-Derived Drugs Based on β-Adrenergic Agents and Nucleosides

Newman¹

2016

Journal of the Brazilian Chemical Society

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This relatively short review demonstrates the very important role of the structures of the natural products adrenaline and relatives, in the design and subsequent approval of β-agonists and antagonists, and of modified nucleosides as anticancer, and in particular, antiviral agents against herpes (HSV), human immunodeficiency virus (HIV) and hepatitis C virus (HCV) that would not have been synthesized in the absence of knowledge of bioactive arabinose nucleosides.

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“…5 /ml (derived from 12 patients, as described above) were cultured in 25 cm 2 cell culture flasks in a final volume of 10 ml. During incubation, cells were cultured in medium consisting of 87% RPMI-1640 (Gibco, Paisley Scotland, UK), 2.5% 1 M HEPES (Gibco) and 10% foetal bovine serum (Gibco).…”

Section: Culture Of Cells With Cytostatic Drugs Cells 1x10mentioning

confidence: 99%

“…Daunorubicin exerts its effect in the cell nucleus by interaction with DNA and the enzyme, topoisomerase (topo) II·. Ara-C is a nucleoside analogue that requires phosphorylation to ara-CTP to become an active cytotoxic drug (2). Similarly to daunorubicin, ara-C exerts its effect in the cell nucleus and causes DNA damage by incorporation into the DNA molecule (3).…”

Section: Introductionmentioning

confidence: 99%

Topoisomerase IIα expression in acute myeloid leukaemia cells that survive after exposure to daunorubicin or ara-C

Tina¹

2009

Oncol Rep

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Abstract. Patients diagnosed with acute myeloid leukaemia are often treated with a combination of daunorubicin and 1-ß-D-arabinofuranosylcytosine (ara-C). Both daunorubicin and ara-C exert their effects in the cell nucleus but by different mechanisms, i.e. daunorubicin causes double stranded DNA breaks by inhibition of the nuclear enzyme, topoisomerase (topo) II·, whereas ara-C is an anti-metabolite that integrates with DNA during DNA synthesis and causes cell cycle arrest. Despite the initial efficacy of these drugs, resistance often develops in the clinical setting. The mechanisms underlying clinical resistance to these drugs are poorly understood, but may be associated with an increase in the proportion of topo II· negative cells. Therefore, the aim of this study was to determine whether daunorubicin treatment results in increased numbers of topo II· negative subpopulations in vitro. Acute myeloid leukaemia cells isolated from 12 consenting patients were treated for 24 h with increasing concentrations of daunorubicin or ara-C and the proportion of topo II·-negative cells in surviving cell populations determined by flow cytometry. Treatment with daunorubicin, but not ara-C, resulted in a significant increase in the proportion of topo II· negative cells (p=0.0023). These results suggest that daunorubicin may act by cell cycle arrest and/or by selection of pre-existing topo II· negative subpopulations. Both of these mechanisms can theoretically contribute to a reduced efficacy of a second dose of daunorubicin. The clinical relevance of these interactions should be further elucidated in experimental and clinical studies. IntroductionA combination of daunorubicin and 1-ß-D-arabinofuranosylcytosine (ara-C) is the standard induction treatment for acute myeloid leukaemia (AML) (1). Daunorubicin exerts its effect in the cell nucleus by interaction with DNA and the enzyme, topoisomerase (topo) II·. Ara-C is a nucleoside analogue that requires phosphorylation to ara-CTP to become an active cytotoxic drug (2). Similarly to daunorubicin, ara-C exerts its effect in the cell nucleus and causes DNA damage by incorporation into the DNA molecule (3). Unfortunately, only 50-60% of patients treated with cytostatic drugs such as daunorubicin and ara-C will enter complete remission, and the long-term survival rate is only 10-20% (1). A major reason for this poor outcome is believed to be a result of intrinsic or acquired resistance to cytostatic drugs.Several cellular mechanisms have been identified that are involved in drug resistance. One mechanism that may play a key role in resistance to daunorubicin is expression of the target molecule, topo II·. Topo II· changes the tertiary structure of DNA and plays an essential role during transcription and duplication of DNA (4). To act as a functional enzyme it requires dimerisation, mainly in the form of homodimerisation. The topo II· dimer causes DNA double-strand breaks that are fixed by disulphide bonds, the so-called cleavable complex. Under ATP hydrolysis the DNA break is religate...

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A proposed mechanism of action of 1-β-d-arabinofuranosyl-cytosine as an inhibitor of the growth of leukemic cells

Cited by 258 publications

References 7 publications

Antiviral Activity of Arabinosylthymine in Herpesviral Replication: Mechanism of Action In Vivo and In Vitro

Antiviral Activity of Arabinosylthymine in Herpesviral Replication: Mechanism of Action In Vivo and In Vitro

Natural Product-Derived Drugs Based on β-Adrenergic Agents and Nucleosides

Topoisomerase IIα expression in acute myeloid leukaemia cells that survive after exposure to daunorubicin or ara-C

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