Cancer Chemotherapy and Pharmacology

, Volume 24, Issue 4, pp 203–210 | Cite as

Pharmacodynamic and DNA methylation studies of high-dose 1-β-d-arabinofuranosyl cytosine before and after in vivo 5-azacytidine treatment in pediatric patients with refractory acute lymphocytic leukemia

  • Vassilios I. Avramis
  • Robert A. Mecum
  • Jonathan Nyce
  • David A. Steele
  • John S. Holcenberg
Original Articles Pharmacodynamics, DNA Methylation, Cytosine Arabinoside, 5-Azacytidine, Lymphocytic Leukemia
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Accepted:

Summary

The primary development of clinical resistance to 1-β-d-arabinofuranosyl cytosine (ara-C) in leukemic blast cells is expressed as decreased cellular concentrations of its active anabolite. Correlations exist between the cellular concentrations of 1-β-d-arabinofuranosyl cytosine 5′-triphosphate (ara-CTP) in leukemic blast cells and inhibition of DNA synthetic capacity with the clinical response to high-dose cytosine arabinoside (HDara-C). 5-Azacytidine (5-Aza-C) and its congeners are potent DNA hypomethylating agents, an action closely associated with the reexpression of certain genes such as that for deoxycytidine kinase (dCk) in ara-C-resistant mouse and human leukemic cells. Reexpression of dCk could increase the cellular ara-CTP concentrations and the sensitivity to ara-C. A total of 17 pediatric patients with refractory acute lymphocytic leukemia (ALL) received a continuous influsion of 5-Aza-C at 150 mg/m2 daily for 5 days after not responding to (13/17) or relapsing from (4/17) an HDara-C regimen (3 g/m2 over 3 h, every 12 h, x 8 doses). Approximately 3 days after the end of the 5-Aza-C infusion, the HDara-C regimen was given again with the idea that the induced DNA hypomethylation in the leukemic cells may have increased the dCk activity and that a reversal of the tumor drug resistance to ara-C could have occurred. Deoxycytidine kinase (expressed as cellular ara-CTP concentrations) in untreated blasts, DNA synthetic capacity (DSC), and the percentage of DNA methylcytidine levels were determined before and after 5-Aza-C administration. Cellular ara-CTP was enhanced to varying degrees in 15 of 16 patients after 5-Aza-C treatment. The average cellular concentration of ara-CTP determined in vitro by the sensitivity test was 314±390 μM, 2.3-fold higher than the average value before 5-Aza-C treatment. In 12 patients in whom the DNA methylation studies were completed before and after 5-Aza-C treatment, the average DNA hypomethylation level was 55.6%+15.8% of pretreatment values (n=13; mean ± SD). DSC showed a profound decline in 2/9 evaluable patients who achieved a complete response (CR) after this regimen. The data suggest that treatment with a cytostatic but DNA-modulatory regimen of 5-Aza-C causes DNA hypomethylation in vivo, which is associated with dCk reexpression in the patients' leukemic blasts. The partial reversal of drug resistance to ara-C by 5-Aza-C yielded two CRs in this poor-prognosis, multiply relapsed patient population with refractory ALL. The data indicate that the 5-Aza-C plus HDara-C regimen may have a profound effect on controlling leukemia refractory to ara-C in patients.

Keywords

Acute Lymphocytic Leukemia Cytosine Arabinoside Cellular Concentration Hypomethylating Agent Deoxycytidine Kinase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations used

ara-C

1-β-d-arabinofuranosyl cytosine

ara-CTP

1-β-d-arabinofuranosyl cytosine 5′-triphosphate

5-Aza-C

5-Azacytidine

HDara-C

high-dose ara-C

mC

5-methyl cytosine

PCA

perchloric acid

PBS

phosphate-buffered saline

dCk

deoxycytidine kinase

SAX

strong anion exchange

SCX

strong cation exchange

DSC

DNA synthetic capacity

t1/2

elimination half-life

BM

bone marrow

PBC

peripheral blast cells

dThd

thymidine

ALL

acute lymphocytic leukemia

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Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • Vassilios I. Avramis
    • 1
  • Robert A. Mecum
    • 1
  • Jonathan Nyce
    • 1
  • David A. Steele
    • 1
  • John S. Holcenberg
    • 1
  1. 1.Division of Hematology-Oncology, Department of Pediatrics, School of MedicineUniversity of Southern California, Childrens Hospital of Los AngelesLos AngelesUSA

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