WR-1065, the active form of amifostine, protects HL-60 cells but not peripheral blood mononuclear cells from radiation and etoposide-induced apoptosis.
OBJECTIVE
Developing myeloid cells are particularly sensitive to chemotherapy and ionizing radiation. Mature cells of the hematopoietic lineages, such as are found in the peripheral blood mononuclear cells (PBMCs), are much less sensitive for reasons that are not yet understood. Protecting the myeloid precursors from radiation or chemotherapy is an important goal.


METHODS
We have used fluorescence microscopy to assess the ability of WR-1065, the active metabolite of amifostine (Ethyol), to protect cultured myeloid leukemic HL-60 cells or freshly isolated PBMCs from the induction of apoptosis by ionizing radiation or etoposide.


RESULTS
WR-1065 greatly reduced the percentage of radiation-induced apoptosis in the p53 negative HL-60 cells 24 h after exposure to 8 Gy. WR-1065 also greatly reduced the percentage of HL-60 cells undergoing apoptosis 24 h after a 1-h exposure to 1 microM etoposide. The pan-caspase inhibitor ZVAD-fmk completely inhibited radiation-induced apoptosis in HL-60 cells when present for the first hour after exposure to radiation, but had no effect on cell survival. In contrast, neither WR-1065 nor ZVAD-fmk reduced the level of radiation-induced apoptosis in normal human PBMCs.


CONCLUSIONS
These results suggest that pro-apoptotic pathways are present in immature myeloid cells that can be selectively protected from radiation or chemotherapy-induced apoptosis.
Hatoum
Georges F
GF
Department of Radiation Oncology, Upstate Medical University, Syracuse, NY 13210, USA.
Nevaldine
Barbara
B
Bhavsar
Tej
T
Phung
Quentin
Q
Hahn
Peter J
PJ
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D002470:Cell Survival; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D018922:HL-60 Cells / Q000187:drug effects* / Q000528:radiation effects*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000528:radiation effects*; D008624:Mercaptoethylamines / Q000494:pharmacology*; D011837:Radiation-Protective Agents / Q000494:pharmacology*
D000590:Amino Acid Chloromethyl Ketones; D000972:Antineoplastic Agents, Phytogenic; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D008624:Mercaptoethylamines; D011837:Radiation-Protective Agents; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; D005047:Etoposide