The molecular and cellular basis of radiosensitivity: implications for understanding how normal tissues and tumors respond to therapeutic radiation.
We have provided an overview of recent studies that have greatly expanded our knowledge of the molecular and cellular mechanisms that determine the sensitivity or resistance to ionizing radiation. Much of this knowledge was obtained by studying tumor and nontumor cell types that under- or overexpress proteins involved in the regulation of the DNA damage response, cell cycle progression, growth factor signal transduction, and apoptosis. These findings may ultimately be useful in devising new strategies to improve the therapeutic ratio in cancer treatment. Despite the rapid advances in knowledge of cellular functions that affect radiosensitivity, we still cannot account for most of the clinically observed heterogeneity of normal tissue and tumor responses to radiotherapy; nor can we accurately predict which individual tumors will be locally controlled and which patients will develop more severe normal tissue damage after radiotherapy. However, several candidate genes for which deletion or loss of function mutations may be associated with altered cellular radiosensitivity (e.g., ATM, p53, BRCA2) have been identified. Some of the differences in normal tissue sensitivity to radiation may occur because of mutations with milder effects, heterozygosity, or polymorphisms of these genes. Finally, molecular mechanisms linking genetic instability, radiosensitivity, and predisposition to cancer are being examined.
Rosen
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Department of Radiation Oncology, Long Island Jewish Medical Center, Albert Einstein College of Medicine, New Hyde Park, New York, USA.
Fan
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Rockwell
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Goldberg
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D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000502:physiology; D016466:CHO Cells / Q000528:radiation effects; D002453:Cell Cycle / Q000528:radiation effects; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000528:radiation effects; D002477:Cells / Q000528:radiation effects*; D006224:Cricetinae; D016207:Cytokines / Q000502:physiology; D004247:DNA / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins; D005796:Genes / Q000528:radiation effects; D019398:Genes, BRCA1; D016158:Genes, p53; D006133:Growth Substances / Q000235:genetics / Q000502:physiology; D006801:Humans; D009369:Neoplasms / Q000532:radiotherapy*; D009381:Neoplasms, Radiation-Induced / Q000209:etiology; D015513:Oncogene Proteins / Q000502:physiology; D009857:Oncogenes / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011836:Radiation Tolerance / Q000235:genetics; D011878:Radiotherapy / Q000009:adverse effects; D015398:Signal Transduction / Q000528:radiation effects; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D025521:Tumor Suppressor Proteins
D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D006133:Growth Substances; D015513:Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D004247:DNA; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases