Cytosine Arabinoside Deamination in Human Leukaemic Myeloblasts and Resistance to Cytosine Arabinoside Therapy

Harris, Adrian L.; Grahame‐Smith, D. G.; Potter, C. W.; Bunch, C

doi:10.1042/cs0600191

Cited by 17 publications

(3 citation statements)

References 16 publications

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“…Downregulation of dCK activity in ara-Cresistant cells has been shown to correlate with hypermethylation of the promoter region of the gene [47]. Moreover, dCK activity may be regulated posttranslationally, since this enzyme is feedback-inhibited by deoxynucleoside triphosphates (dNTPs) and by some phosphorylated analogs such as ara-CTP [48].…”

Section: Dck Deficiencymentioning

confidence: 98%

Problems Related to Resistance to Cytarabine in Acute Myeloid Leukemia

Cros

Jordheim

Dumontet

et al. 2004

Leukemia & Lymphoma

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First-line chemotherapy treatment in acute-myeloid leukemia patients usually consists of a combination of cytarabine (ara-C) and an anthracycline. These regimens induce complete response (CR) rates in 65-80% of newly diagnosed AML patients. However, clinical outcome is unsatisfactory, as most of the patients who achieve a CR will relapse within 2 years from diagnosis, often with resistant disease and poor response to subsequent therapy. Thus, understanding the factors which contribute to the emergence of chemoresistant leukemic cells is essential to improve outcome in patients suffering from this disease. In this review, we highlight the current knowledge concerning the cellular mechanisms of resistance to ara-C. We also discuss possible strategies that may be used to overcome such resistance. Efforts to increase intracellular levels and DNA incorporation of phosphorylated ara-C using pronucleotides of ara-C are very promising. Ara-C combined with agents modulating apototic responses are expected to provide additional benefit. In the same way that combination chemotherapy has provided curative treatment of AML, a multifactorial approach of ara-C resistance should allow significant progress in the treatment of currently chemoresistant disease.

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Section: Dck Deficiencymentioning

confidence: 98%

Problems Related to Resistance to Cytarabine in Acute Myeloid Leukemia

Cros

Jordheim

Dumontet

et al. 2004

Leukemia & Lymphoma

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“…4 shows little araU formation by intact lymphoblasts, so that excessive deamination of araC cannot explain the low araCTP accumulation by lymphoblasts. In two studies the rate of araC deamination in leukemic blast cells was found to be unrelated to' the extent of araC phosphorylation measured either by araCTP formation (in intact cells) or deoxycytidine kinase assays (on broken cells) from different patients (22,40,42). Thus, none of the assays of enzymes metabolizing araC provide a satisfactory explanation for the sixfold range in araCTP accumulation by different leukemic blasts.…”

Section: Discussionmentioning

confidence: 97%

Cytosine arabinoside transport and metabolism in acute leukemias and T cell lymphoblastic lymphoma.

Wiley¹,

Taupin²,

Jamieson³

et al. 1985

J. Clin. Invest.

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Cytosine arabinoside (araC) has proven efficacy in acute myeloid leukemia (AML), but its place in the treatment of acute lymphoblastic leukemia (ALL) and T lymphoblastic lymphoma is uncertain. The therapeutic potential of araC has been assessed in patients with AML, ALL, and T lymphoblastic lymphoma by measuring the conversion of araC to its active metabolite, the 5-triphosphate of araC (araCTP), in purified blasts from patients as well as in normal polymorphs and lymphocytes. In all leukemias, araCTP was the major intracellular metabolite of araC. The highest araCTP formation was in blasts from T lymphoblastic lymphoma, which formed threefold more nucleotide than myeloblasts, and in turn myeloblasts formed twofold more araCTP than lymphoblasts from ALL. The mean araCTP formation in myeloblasts was sixfold greater than polymorphs, but in contrast, lymphoblasts and lymphocytes formed low and similar amounts of this nucleotide. Reasons for the sixfold range in araCTP accumulation in the various leukemic blasts were studied.

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“…10,11 Troxacitabine undergoes phosphorylation to its mono-, di-, and triphosphate forms and is incorporated into DNA but not RNA. [23][24][25] Troxacitabine has a unique pattern of cellular uptake and metabolism. 14 Troxacitabine is a complete DNA chain terminator, probably because the dioxolane ring of its structure lacks the necessary hydroxyl moiety for chain elongation (Fig 1).…”

Section: Discussionmentioning

confidence: 99%