title: Mechanisms of resistance to high and low linear energy transfer radiation in myeloid leukemia cells.
abstract: Low linear energy transfer (LET) ionizing radiation (IR) is an important form of therapy for acute leukemias administered externally or as radioimmunotherapy. IR is also a potential source of DNA damage. High LET IR produces structurally different forms of DNA damage and has emerged as potential treatment of metastatic and hematopoietic malignancies. Therefore, understanding mechanisms of resistance is valuable. We created stable myeloid leukemia HL60 cell clones radioresistant to either γ-rays or α-particles to understand possible mechanisms in radioresistance. Cross-resistance to each type of IR was observed, but resistance to clustered, complex α-particle damage was substantially lower than to equivalent doses of γ-rays. The resistant phenotype was driven by changes in: apoptosis; late G2/M checkpoint accumulation that was indicative of increased genomic instability; stronger dependence on homology-directed repair; and more robust repair of DNA double-strand breaks and sublethal-type damage induced by γ-rays, but not by α-particles. The more potent cytotoxicity of α-particles warrants their continued investigation as therapies for leukemia and other cancers.
authors: Molecular Pharmacology and Chemistry Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors: Kurtis J
authors: KJ
authors: Haro
authors: Andrew C
authors: AC
authors: Scott
authors: David A
authors: DA
authors: Scheinberg
mesh_terms: D000512:Alpha Particles / Q000009:adverse effects*; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D002999:Clone Cells; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects*; D004260:DNA Repair; D004307:Dose-Response Relationship, Radiation; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics / Q000528:radiation effects; D005720:Gamma Rays / Q000009:adverse effects*; D018922:HL-60 Cells; D006801:Humans; D018499:Linear Energy Transfer; D034741:RNA, Small Interfering / Q000235:genetics; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D051135:Rad51 Recombinase