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Metabolism of ara-C by blast cells from patients with ANLL.

Publication ,  Journal Article
Ross, DD; Thompson, BW; Joneckis, CC; Akman, SA; Schiffer, CA
Published in: Blood
July 1986

The dose-response relationship between extracellular concentration of cytosine arabinoside (ara-C) and intracellular formation of the putative active metabolites of ara-C [ara-C incorporation into DNA and intracellular pools of ara-C in triphosphate form (ara-CTP)] was investigated in blast cells obtained from patients with acute nonlymphocytic leukemia (ANLL) by exposing these cells in vitro to 10, 100, or 1,000 nmol/L of ara-C. We studied 23 untreated patients who subsequently achieved complete remission (CR) with a regimen using daunorubicin and conventional doses of ara-C (ara-C-sensitive group), and 30 patients judged to be ara-C-resistant either by failing initial induction therapy (16 patients) or by having relapsed on an ara-C-containing maintenance regimen (14 patients). In both patient groups, ara-C incorporation into DNA and intracellular ara-CTP both displayed statistically significant increases in response to increasing extracellular concentrations of ara-C (P = .0001 in both cases), with the rate of increase of ara-CTP greater than that of ara-C incorporation. Moreover, blast cells from all patients, even those who were most clinically resistant to ara-C, were able to form ara-CTP and to incorporate ara-C into DNA. Each tenfold increment in extracellular ara-C concentration caused an 8.5-fold increase in ara-CTP, but only a 3.6-fold increase in ara-C incorporation into DNA. Thus, the efficiency of incorporation of ara-C into DNA (defined as the ratio of ara-C incorporation to ara-CTP pools) decreased by 58% with each tenfold increment in the extracellular concentration of ara-C (P less than .0001), presumably as a result of the inhibitory effect of ara-CTP on DNA polymerase. Using an analysis of covariance, modest differences were found in the levels of the ara-C metabolite variables in the ara-C-sensitive group as compared with the resistant group. However, because there was considerable overlap in ara-C metabolite formation among the patient groups, it was not possible to predict clinical outcome by these in vitro assessments of ara-C metabolism.

Duke Scholars

Published In

Blood

ISSN

0006-4971

Publication Date

July 1986

Volume

68

Issue

1

Start / End Page

76 / 82

Location

United States

Related Subject Headings

  • Middle Aged
  • Male
  • Leukemia
  • Immunology
  • Humans
  • Female
  • Drug Resistance
  • Dose-Response Relationship, Drug
  • DNA, Neoplasm
  • Cytarabine
 

Citation

APA
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ICMJE
MLA
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Ross, D. D., Thompson, B. W., Joneckis, C. C., Akman, S. A., & Schiffer, C. A. (1986). Metabolism of ara-C by blast cells from patients with ANLL. Blood, 68(1), 76–82.
Ross, D. D., B. W. Thompson, C. C. Joneckis, S. A. Akman, and C. A. Schiffer. “Metabolism of ara-C by blast cells from patients with ANLL.Blood 68, no. 1 (July 1986): 76–82.
Ross DD, Thompson BW, Joneckis CC, Akman SA, Schiffer CA. Metabolism of ara-C by blast cells from patients with ANLL. Blood. 1986 Jul;68(1):76–82.
Ross, D. D., et al. “Metabolism of ara-C by blast cells from patients with ANLL.Blood, vol. 68, no. 1, July 1986, pp. 76–82.
Ross DD, Thompson BW, Joneckis CC, Akman SA, Schiffer CA. Metabolism of ara-C by blast cells from patients with ANLL. Blood. 1986 Jul;68(1):76–82.

Published In

Blood

ISSN

0006-4971

Publication Date

July 1986

Volume

68

Issue

1

Start / End Page

76 / 82

Location

United States

Related Subject Headings

  • Middle Aged
  • Male
  • Leukemia
  • Immunology
  • Humans
  • Female
  • Drug Resistance
  • Dose-Response Relationship, Drug
  • DNA, Neoplasm
  • Cytarabine