Biochemical changes associated with the development of resistance to 5‐azacytidine in AKR leukemic mice

Veselý, Jiří; Seifert, Jaroslav; Čihák, A.; Šorm, F.

doi:10.1002/ijc.2910010106

Cited by 14 publications

(8 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of particular interest are the membrane transporters that mediate cellular drug uptake. Early studies in a leukemic mouse model showed a connection between azacytidine resistance and impaired uptake of uridine and cytidine, which supported an important role of cellular transport mechanisms in mediating drug effects 33. However, the role of transport processes in the treatment with azanucleosides has not been characterized on the molecular level yet.…”

Section: Cellular Uptake Of Azanucleosidesmentioning

confidence: 99%

Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine

Stresemann

Lyko

2008

Intl Journal of Cancer

790

694

View full text Add to dashboard Cite

The cytosine analogues 5-azacytosine (azacytidine) and 2 0 -deoxy-5-azacytidine (decitabine) are the currently most advanced drugs for epigenetic cancer therapies. These compounds function as DNA methyltransferase inhibitors and have shown substantial potency in reactivating epigenetically silenced tumor suppressor genes in vitro. However, it has been difficult to define the mode of action of these drugs in patients and it appears that clinical responses are influenced both by epigenetic alterations and by apoptosis induction. To maximize the clinical efficacy of azacytidine and decitabine it will be important to understand the molecular changes induced by these drugs. In this review, we examine the pharmacological properties of azanucleosides and their interactions with various cellular pathways. Because azacytidine and decitabine are prodrugs, an understanding of the cellular mechanisms mediating transmembrane transport and metabolic activation will be critically important for optimizing patient responses. We also discuss the mechanism of DNA methyltransferase inhibition and emphasize the need for the identification of predictive biomarkers for the further advancement of epigenetic therapies. ' 2008 Wiley-Liss, Inc.Key words: azacytidine; decitabine; DNA methyltransferase; DNA methylation; cancer More than 40 years ago, the azanucleosides 5-azacytidine (azacytidine) and 2 0 -deoxy-5-azacytidine (decitabine) were developed as classical cytostatic agents. 1 Several years later, it was shown that these compounds inhibit DNA methylation in human cell lines, which provided a mechanistic explanation for their differentiation-modulating activity. 2 In addition, this observation also initiated the development of azanucleosides as epigenetic drugs. After substantial refinements in their clinical dosing schedules, both azacytidine and decitabine have now shown significant clinical benefits in the treatment of myelodysplastic syndrome (MDS), a preleukemic bone marrow disorder. 3,4 As a consequence, these drugs have now received FDA approval for the treatment of MDS. There are substantial ongoing efforts to identify and develop novel DNA methyltransferase inhibitors. 5,6 However, the currently available compounds appear to have weaker gene reactivation potencies than azanucleosides 7,8 and none of the candidate drugs has reached an advanced clinical testing stage for epigenetic indications yet. This has established azacytidine and decitabine as archetypal drugs for epigenetic cancer therapies. 9 Despite the renewed interest in azacytidine and decitabine, surprisingly little is known about the molecular mode of action of these drugs. It is clear that azanucleosides have cytotoxic effects and that they can cause DNA demethylation, but the relationships between these characteristics and their respective significance for clinical responses has not been established yet. A comprehensive understanding of drug characteristics will be critically important for defining their modes of action and to further advance their clinical de...

show abstract

Section: Cellular Uptake Of Azanucleosidesmentioning

confidence: 99%

Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine

Stresemann

Lyko

2008

Intl Journal of Cancer

790

694

View full text Add to dashboard Cite

show abstract

“…The enzyme has attracted considerable interest because of its pharmacological importance in experimental cancer chemotherapy with uridine (Pasternak et al, 1961;Reichard et al, 1962) and cytidine (Vesely et al, 1970) analogues that are converted into biologically active 5'-phosphates. During the development of resistance towards uridine and cytidine antimetabolites uridine kinase activity has been found in some cases to be partially deleted, and this impairment is often considered as the metabolic deviation underlying the change to resistance (Brockman, 1963).…”

Section: Discussionmentioning

confidence: 99%

“…Previously we have studied uridine kinase in mouse and adult rat liver under different experimental conditions. Although the activity of the enzyme from livers of leukaemic mice made resistant to 5-azacytidine is diminished in comparison with its counterpart from livers of the parental leukaemic line of mice (Vesely et al, 1970), the activity of uridine kinase from normal adult rat liver is markedly enhanced after the administration of 5-azacytidine (Cihak et al, 1972). Both enzyme preparations are more stable on heating than the respective controls.…”

mentioning

confidence: 99%

Uridine kinase in embryonic rat liver. Modulation of enzyme activity by 5-azacytidine

Veselý

Čihák

1973

Biochemical Journal

Self Cite

View full text Add to dashboard Cite

Uridine kinase activity in rat liver decreases during embryonic and postnatal development. Administration of 5-azacytidine enhances liver uridine kinase activity in adult rats, but depresses it in embryos. The liver enzymes from the foetus and the adult are precipitated at different (NH(4))(2)SO(4) concentrations although they are eluted at about the same position on chromatography on a column of Sepharose 6B.

show abstract

“…It was observed that resistance of 5-AzCR was achieved rapidly in the AK mouse leukemia and was cross-resistant to 5-fluorouraciI. In the resistant tumors there was less inhibition of the incorporation of orotic acid into the nucleic acids, less uridine kinase, and less uridine phosphorylase activity than in the sensitive cells (132). 5-Iodo-2'-deoxyuridine (I UdR).-The synthesis of this nucleoside (X, Fig.…”

Section: Purine Analoguesmentioning

confidence: 96%

Cancer Chemotherapy with Purine and Pyrimidine Analogues

Heidelberger¹

1967

Annu. Rev. Pharmacol.

View full text Add to dashboard Cite

Biochemical changes associated with the development of resistance to 5‐azacytidine in AKR leukemic mice

Abstract: Resistance to 5-azacytidine, a

Cited by 14 publications

References 7 publications

Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine

Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine

Uridine kinase in embryonic rat liver. Modulation of enzyme activity by 5-azacytidine

Cancer Chemotherapy with Purine and Pyrimidine Analogues

Contact Info

Product

Resources

About