Pharmacodynamic and DNA methylation studies of high-dose 1-beta-D-arabinofuranosyl cytosine before and after in vivo 5-azacytidine treatment in pediatric patients with refractory acute lymphocytic leukemia.
The primary development of clinical resistance to 1-beta-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-beta-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 infusion 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 microM, 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.(ABSTRACT TRUNCATED AT 400 WORDS)
Avramis
V I
VI
Department of Pediatrics, School of Medicine, University of Southern California, Childrens Hospital of Los Angeles 90027.
Mecum
R A
RA
Nyce
J
J
Steele
D A
DA
Holcenberg
J S
JS
D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D001374:Azacitidine / Q000008:administration & dosage; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine / Q000008:administration & dosage / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism*; D003842:Deoxycytidine Kinase / Q000235:genetics; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D008745:Methylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D012074:Remission Induction; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D004273:DNA, Neoplasm; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D003842:Deoxycytidine Kinase; D001374:Azacitidine