Combined antileukemic activity of pIXY 321 and Ara-C against human acute myeloid leukemia cells.
Prolonged administration of conventional (100 mg/m2/day) or low dose Ara-C (20 mg/m2/day) has been associated with significant clinical antileukemic effects in AML and myelodysplastic syndromes. These doses and schedules of Ara-C yield plasma Ara-C concentrations in the range of 10 to 100 nM. Utilizing concentrations and a schedule of Ara-C treatment, representative of Ara-C exposures in these clinical situations, we performed in vitro studies to examine the effects of co-treatment with pIXY 321 on Ara-C induced apoptosis and Ara-C-mediated colony growth inhibition of human myeloid leukemia HL-60 cells. Significantly greater internucleosomal DNA fragmentation, higher percentage of morphologically recognizable apoptotic cells and increased colony growth inhibition were observed following treatment with 100 versus 10 nM Ara-C for 5 days. Simultaneous exposure to 10 ng/ml pIXY 321 resulted in significantly increased colony growth inhibition as well as DNA fragmentation and apoptosis due to 10 nM but not 100 nM Ara-C. These concentrations of Ara-C inhibited c-myc and did not induce c-jun mRNA expression. These effects of Ara-C on c-myc and c-jun expressions were not influenced by co-treatment with pIXY 321. Neither treatment with pIXY 321 or Ara-C alone, nor co-treatment with pIXY 321 and Ara-C, significantly altered the intracellular p26BCL-2 levels in HL-60 cells. These results indicate that co-treatment with pIXY 321 significantly increases low dose Ara-C-induced apoptosis and thereby its antileukemic activity.
Tang
C
C
Department of Medicine, Medical University of South Carolina, Charleston 29425.
Huang
Y
Y
Ponnathpur
V S
VS
Ray
S
S
Mahoney
M E
ME
Bullock
G
G
Ibrado
A M
AM
Bhalla
K
K
D000208:Acute Disease; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015152:Blotting, Northern; D015153:Blotting, Western; D003561:Cytarabine / Q000008:administration & dosage*; D004273:DNA, Neoplasm / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage*; D006801:Humans; D007377:Interleukin-3 / Q000008:administration & dosage*; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D009707:Nucleosomes / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D007377:Interleukin-3; D009707:Nucleosomes; C078524:PIXY321 fusion protein, recombinant; D011993:Recombinant Fusion Proteins; D003561:Cytarabine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor