Abstract
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 μM/L) failed to cause this effect, while higher concentrations (≥2200 μM/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 μM/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.
Original language | English (US) |
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Pages (from-to) | 1640-1647 |
Number of pages | 8 |
Journal | Experimental Hematology |
Volume | 21 |
Issue number | 13 |
State | Published - 1993 |
Externally published | Yes |
Keywords
- 4-HC
- Apoptosis
- Interleukin-3
- Interleukin-6
- bcl-2
ASJC Scopus subject areas
- Molecular Biology
- Hematology
- Genetics
- Cell Biology
- Cancer Research