Enzymology of Purine and Pyrimidine Antimetabolites Used in the Treatment of Cancer

Parker, William B.

doi:10.1021/cr900028p

Cited by 544 publications

(366 citation statements)

References 86 publications

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“…Aza-dCyd is metabolically activated in vivo through consecutive phosphorylations, into aza-dCTP that is readily incorporated into DNA and extended by the DNA polymerase (3). Once in DNA, aza-dCyd acts as a suicidal substrate by covalently trapping DNA methyltransferase (DNMT) molecules that attempt to initiate cytosine methylation.…”

Section: Introductionmentioning

confidence: 99%

“…It is well established that decitabine treatment induces the activation of a specific DNA damage response that includes the phosphorylation of histone H2AX (7). Additionally, the cytotoxic and mutagenic properties of decitabine may be partially derived from its intrinsic chemical instability once it is incorporated into DNA or by the accumulation of DNA repair intermediates (3). Recently, it has been proposed that the base excision repair mechanism (BER) might be initiating the repair of decitabine-induced DNA base lesions although the precise nature of the damage or the DNA glycosylases involved remains unknown (11).…”

Section: Introductionmentioning

confidence: 99%

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The nucleotidohydrolases DCTPP1 and dUTPase are involved in the cellular response to decitabine

Requena

Pérez-Moreno

Horváth

et al. 2016

Biochemical Journal

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Decitabine (5-aza-2′-deoxycytidine, aza-dCyd) is an anti-cancer drug used clinically for the treatment of myelodysplastic syndromes and acute myeloid leukaemia that can act as a DNA-demethylating or genotoxic agent in a dose-dependent manner. On the other hand, DCTPP1 (dCTP pyrophosphatase 1) and dUTPase are two ‘house-cleaning’ nucleotidohydrolases involved in the elimination of non-canonical nucleotides. In the present study, we show that exposure of HeLa cells to decitabine up-regulates the expression of several pyrimidine metabolic enzymes including DCTPP1, dUTPase, dCMP deaminase and thymidylate synthase, thus suggesting their contribution to the cellular response to this anti-cancer nucleoside. We present several lines of evidence supporting that, in addition to the formation of aza-dCTP (5-aza-2′-deoxycytidine-5′-triphosphate), an alternative cytotoxic mechanism for decitabine may involve the formation of aza-dUMP, a potential thymidylate synthase inhibitor. Indeed, dUTPase or DCTPP1 down-regulation enhanced the cytotoxic effect of decitabine producing an accumulation of nucleoside triphosphates containing uracil as well as uracil misincorporation and double-strand breaks in genomic DNA. Moreover, DCTPP1 hydrolyses the triphosphate form of decitabine with similar kinetic efficiency to its natural substrate dCTP and prevents decitabine-induced global DNA demethylation. The data suggest that the nucleotidohydrolases DCTPP1 and dUTPase are factors involved in the mode of action of decitabine with potential value as enzymatic targets to improve decitabine-based chemotherapy.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The nucleotidohydrolases DCTPP1 and dUTPase are involved in the cellular response to decitabine

Requena

Pérez-Moreno

Horváth

et al. 2016

Biochemical Journal

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“…Chemically modified purine and pyrimidine nucleosides (nucleoside analogs (NAs)) 5 represent about 20% of all chemotherapeutics currently used in cancer treatment (1). NAs mimic the natural nucleic acid building blocks and act as antimetabolites interfering with tumor cell nucleoside/nucleotide metabolism and/or DNA/RNA synthesis.…”

mentioning

confidence: 99%

Nucleoside-catabolizing Enzymes in Mycoplasma-infected Tumor Cell Cultures Compromise the Cytostatic Activity of the Anticancer Drug Gemcitabine

Voorde

Sabuncuoğlu

Noppen

et al. 2014

Journal of Biological Chemistry

125

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Background: Gemcitabine is used to treat solid tumors. Some mycoplasmas preferentially colonize tumors in patients. Results: Mycoplasma-encoded cytidine deaminase and pyrimidine nucleoside phosphorylase compromise the cytostatic/antitumor activity of gemcitabine in mycoplasma-infected tumor cell cultures and xenografts in mice. Conclusion: Tumor-associated mycoplasmas may decrease the therapeutic efficiency of gemcitabine. Significance: Current treatment of mycoplasma-infected tumors with gemcitabine may be suboptimal.

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“…Inhibitors of DNA synthesis inhibit essential biosynthetic processes or are incorporated into macromolecules (DNA and RNA). These drugs are either structural analogues for heterocyclic bases or agents interfering with folate metabolism (heterocyclic bases and folic acid are DNA building blocks) and they inhibit main steps in the formation of purine and pyrimidine bases as well as nucleotides (Parker, 2009). This class of agent includes antifolates (methotrexate, pemetrixed) (Goldman et al, 2010), antipyrimidines (5-fluorouracil, capecitabine, eniluracile, hydroxyurea) (Longley et al, 2003) and antipurines (6-mercaptopurine, 6-thioguanine).…”

Section: Anticancer Drugsmentioning

confidence: 99%

Anticancer Drug Metabolism: Chemotherapy Resistance and New Therapeutic Approaches

Akhdar¹,

Legendre²,

Aninat³

et al. 2012

Topics on Drug Metabolism

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Enzymology of Purine and Pyrimidine Antimetabolites Used in the Treatment of Cancer

Cited by 544 publications

References 86 publications

The nucleotidohydrolases DCTPP1 and dUTPase are involved in the cellular response to decitabine

The nucleotidohydrolases DCTPP1 and dUTPase are involved in the cellular response to decitabine

Nucleoside-catabolizing Enzymes in Mycoplasma-infected Tumor Cell Cultures Compromise the Cytostatic Activity of the Anticancer Drug Gemcitabine

Anticancer Drug Metabolism: Chemotherapy Resistance and New Therapeutic Approaches

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