Effect of combined treatment with interleukin-3 and interleukin-6 on 4-hydroperoxycyclo-phosphamide-induced programmed cell death or apoptosis in human myeloid leukemia cells.
In autologous bone marrow transplantation in patients with acute myeloid leukemia (AML), 4-hydroperoxycyclophosphamide (4-HC) is a commonly used ex vivo purging agent for leukemic blasts. In the present report, we demonstrate that exposure to high concentrations of 4-HC for 1 hour, as used in ex vivo bone marrow purging, produces internucleosomal DNA fragmentation characteristic of apoptosis, or programmed cell death (PCD), in human myeloid leukemia HL60 cells. Lower concentrations of 4-HC (10, 20, or 50 microM/L) failed to cause this effect, while higher concentrations (> or = 200 microM/L) produced random DNA fragmentation. 4-HC-mediated internucleosomal DNA fragmentation was associated with a marked induction in c-jun and significant reductions in bcl-2 and c-myc oncogene expressions. A combined treatment with interleukin-3 (IL-3) plus IL-6 for 18 hours before an additional, 1-hour concurrent treatment with 4-HC (100 microM/L) significantly increased 4-HC-induced DNA fragmentation as well as colony growth inhibition of HL60 cells. The effects of cotreatment with IL-3 plus IL-6 were also associated with a further, modest decrease in bcl-2 and c-myc and augmentation of c-jun expression. These findings highlight an alternative mechanism of 4-HC-induced leukemic cell death that can be potentially enhanced by cotreatment with IL-3 plus IL-6.
Bullock
G
G
Division of Hematology/Oncology, Medical University of South Carolina, Charleston 29425.
Tang
C
C
Tourkina
E
E
Ibrado
A M
AM
Lutzky
J
J
Huang
Y
Y
Mahoney
M E
ME
Bhalla
K
K
D017209:Apoptosis / Q000187:drug effects*; D015139:Blotting, Southern; D016465:Bone Marrow Purging; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000378:metabolism; D015870:Gene Expression; D016758:Genes, jun; D016259:Genes, myc; D006801:Humans; D007377:Interleukin-3 / Q000008:administration & dosage / Q000494:pharmacology*; D015850:Interleukin-6 / Q000008:administration & dosage / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000473:pathology*; D012334:RNA, Neoplasm / Q000032:analysis; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D007377:Interleukin-3; D015850:Interleukin-6; D012334:RNA, Neoplasm; D003520:Cyclophosphamide; C011272:perfosfamide