ATM as a target for novel radiosensitizers.
DNA damage checkpoints are complex signal transduction pathways that are critical for normal cellular recovery following potentially lethal genotoxic insults. The ataxia-telangiectasia mutated (ATM) protein kinase is a critical component in these pathways and integrates the cellular response to damage by phosphorylating key proteins involved in cell cycle regulation and DNA repair. Lack of normal ATM function in the inherited ataxia-telangiectasia (A-T) syndrome results in a pleiotropic clinical syndrome characterized by a marked increased risk of cancer and profound hypersensitivity to ionizing radiation. Cells derived from patients with A-T share some of these attributes with genomic instability, loss of normal cell cycle arrest pathways, defects in DNA repair and increased radiation sensitivity. The radiosensitivity of A-T cells suggests that pharmacological inhibitors of the ATM kinase should be effective radiosensitizing agents. In fact, caffeine inhibits ATM kinase activity at concentrations that result in an A-T-like phenotype with loss of cell cycle checkpoints and hypersensitivity to ionizing radiation. Although the clinical use of caffeine as a radiosensitizer is limited by potentially lethal systemic toxicities, more potent methyl xanthines may selectively inhibit the ATM pathway at clinically achievable levels. Interestingly, caffeine and other methyl xanthines preferentially radiosensitize cells that lack normal p53 function. Because p53 is commonly inactivated in epithelial malignancies, this suggests that small molecule inhibitors of ATM might selectively sensitize the majority of tumors to the lethal effects of ionizing radiation while sparing normal tissues.
Sarkaria
J N
JN
Department of Oncology, Mayo Foundation, Rochester, MN 55905, USA.
Eshleman
J S
JS
D001260:Ataxia Telangiectasia / Q000235:genetics* / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D002110:Caffeine / Q000494:pharmacology; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002869:Chromosome Aberrations; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins; D006801:Humans; D009369:Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D010431:Pentoxifylline / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics*; D011836:Radiation Tolerance / Q000235:genetics; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D010726:Phosphodiesterase Inhibitors; D011838:Radiation-Sensitizing Agents; D025521:Tumor Suppressor Proteins; D002110:Caffeine; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D010431:Pentoxifylline