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.

[1]  M. Urie,et al.  Proton beams in radiation therapy. , 1992, Journal of the National Cancer Institute.

[2]  D. Goeddel,et al.  TRAF2-mediated activation of NF-kappa B by TNF receptor 2 and CD40 , 1995, Science.

[3]  E. Rosen,et al.  Scatter factor protects epithelial and carcinoma cells against apoptosis induced by DNA-damaging agents , 1998, Oncogene.

[4]  A. Carrano,et al.  Molecular cloning of the human XRCC1 gene, which corrects defective DNA strand break repair and sister chromatid exchange , 1990, Molecular and cellular biology.

[5]  H. Lorenz,et al.  A rapid and simple method for the isolation of apoptotic DNA fragments. , 1994, Nucleic acids research.

[6]  K. Vousden,et al.  Differential activation of target cellular promoters by p53 mutants with impaired apoptotic function , 1996, Molecular and cellular biology.

[7]  G. Nuovo,et al.  Hyperexpression of mitogen-activated protein kinase in human breast cancer. , 1997, The Journal of clinical investigation.

[8]  G. V. Vande Woude,et al.  Synergy between the Mos/mitogen-activated protein kinase pathway and loss of p53 function in transformation and chromosome instability , 1997, Molecular and cellular biology.

[9]  J. Rommens,et al.  The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds , 1996, Nature Genetics.

[10]  J. Rossant,et al.  The Tumor Suppressor Gene Brca1 Is Required for Embryonic Cellular Proliferation in the Mouse , 1996, Cell.

[11]  T Takahashi,et al.  Overexpression of bax sensitizes human breast cancer MCF‐7 cells to radiation‐induced apoptosis , 1996, International journal of cancer.

[12]  K. Caldecott,et al.  XRCC1 polypeptide interacts with DNA polymerase beta and possibly poly (ADP-ribose) polymerase, and DNA ligase III is a novel molecular 'nick-sensor' in vitro. , 1996, Nucleic acids research.

[13]  J. Cleveland,et al.  c-Myc induces apoptosis and cell cycle progression by separable, yet overlapping, pathways. , 1996, Oncogene.

[14]  D. Hallahan,et al.  Increased tumor necrosis factor alpha mRNA after cellular exposure to ionizing radiation. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[15]  D A Scudiero,et al.  Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. , 1988, Cancer research.

[16]  G. Birrell,et al.  Induction of p53 protein by gamma radiation in lymphocyte lines from breast cancer and ataxia telangiectasia patients. , 1995, British Journal of Cancer.

[17]  M. Greaves,et al.  ts BCR-ABL kinase activation confers increased resistance to genotoxic damage via cell cycle block. , 1996, Oncogene.

[18]  R. Weichselbaum,et al.  Role for c-Abl tyrosine kinase in growth arrest response to DNA damage , 1996, Nature.

[19]  R. Muschel,et al.  The molecular basis for cell cycle delays following ionizing radiation: a review. , 1994, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[20]  S. Tucker,et al.  Fibroblast radiosensitivity versus acute and late normal skin responses in patients treated for breast cancer. , 1995, International journal of radiation oncology, biology, physics.

[21]  J. Stone,et al.  Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity , 1995, Nature Medicine.

[22]  D. Hallahan,et al.  Tumor necrosis factor α (TNF-α) gene therapy targeted by ionizing radiation selectively damages tumor vasculature , 1996 .

[23]  C. Snapper,et al.  Synergy of IL-1 and stem cell factor in radioprotection of mice is associated with IL-1 up-regulation of mRNA and protein expression for c-kit on bone marrow cells. , 1994, Journal of immunology.

[24]  Alfred A. Boyd,et al.  Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2 , 1996, Nature Genetics.

[25]  E. Rosen,et al.  Scatter factor and angiogenesis. , 1995, Advances in cancer research.

[26]  G. Evan,et al.  Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB , 1997, Nature.

[27]  I. Wertz,et al.  Diverse molecular provocation of programmed cell death. , 1996, Trends in biochemical sciences.

[28]  M. Evans,et al.  p53 modulation of TFIIH–associated nucleotide excision repair activity , 1995, Nature Genetics.

[29]  R. Bristow,et al.  Mutant p53 increases radioresistance in rat embryo fibroblasts simultaneously transfected with HPV16-E7 and/or activated H-ras. , 1994, Oncogene.

[30]  P. Jeggo,et al.  DNA strand break rejoining defect in xrs-6 is complemented by transfection with the human Ku80 gene. , 1995, Cancer research.

[31]  E. Shaulian,et al.  Induction of apoptosis in HeLa cells by trans-activation-deficient p53. , 1995, Genes & development.

[32]  D. Hallahan,et al.  c-jun and Egr-1 Participate in DNA Synthesis and Cell Survival in Response to Ionizing Radiation Exposure (*) , 1995, The Journal of Biological Chemistry.

[33]  S. Velasco-Miguel,et al.  Induction of the growth inhibitor IGF-binding protein 3 by p53 , 1995, Nature.

[34]  Ralph Scully,et al.  Dynamic Changes of BRCA1 Subnuclear Location and Phosphorylation State Are Initiated by DNA Damage , 1997, Cell.

[35]  P. Bergman,et al.  Radioresistance, chemoresistance, and apoptosis resistance. The past, present, and future. , 1997, The Veterinary clinics of North America. Small animal practice.

[36]  G T Chen,et al.  Implementation of three dimensional conformal radiation therapy: prospects, opportunities, and challenges. , 1995, International journal of radiation oncology, biology, physics.

[37]  M. Oettinger,et al.  DNA-dependent kinase (p350) as a candidate gene for the murine SCID defect , 1995, Science.

[38]  G. Morris Review article: effects of radiation on the cell proliferation kinetics of epithelial tissues--therapeutic implications. , 1996, The British journal of radiology.

[39]  R. Chakraborty,et al.  Cancer predisposition, radiosensitivity and the risk of radiation-induced cancers. II. A Mendelian single-locus model of cancer predisposition and radiosensitivity for predicting cancer risks in populations. , 1995, Radiation research.

[40]  S. Hellman,et al.  Normal tissue responses to radiation therapy. , 1975, The New England journal of medicine.

[41]  J. Trent,et al.  WAF1, a potential mediator of p53 tumor suppression , 1993, Cell.

[42]  E. Rosen,et al.  Scatter factor and the c-met receptor: a paradigm for mesenchymal/epithelial interaction , 1994, The Journal of cell biology.

[43]  K. Kohn,et al.  Role of the p53 tumor suppressor gene in cell cycle arrest and radiosensitivity of Burkitt's lymphoma cell lines. , 1993, Cancer research.

[44]  G. Fletcher Textbook of radiotherapy , 1973 .

[45]  C. Rodríguez,et al.  Interleukin‐1β suppresses apoptosis in CD34 positive bone marrow cells through activation of the type I IL‐1 receptor , 1996, Journal of cellular physiology.

[46]  D. Vaux,et al.  CED-4—The Third Horseman of Apoptosis , 1997, Cell.

[47]  M. Sklar The ras oncogenes increase the intrinsic resistance of NIH 3T3 cells to ionizing radiation. , 1988, Science.

[48]  S. Frisch,et al.  Disruption of epithelial cell-matrix interactions induces apoptosis , 1994, The Journal of cell biology.

[49]  K. Nakagawa,et al.  Radiation therapy for patients with xeroderma pigmentosum. , 1996, Radiation medicine.

[50]  J. Rubin,et al.  Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. , 1991, Science.

[51]  G. H. Weiss,et al.  Urinary and tissue levels of scatter factor in transitional cell carcinoma of bladder. , 1997, The Journal of urology.

[52]  M. Arends,et al.  Increasing the susceptibility of the rat 208F fibroblast cell line to radiation-induced apoptosis does not alter its clonogenic survival dose-response. , 1995, British Journal of Cancer.

[53]  S. Nagata,et al.  Apoptosis by Death Factor , 1997, Cell.

[54]  K. Kohn,et al.  Disruption of p53 function sensitizes breast cancer MCF-7 cells to cisplatin and pentoxifylline. , 1995, Cancer research.

[55]  L. Peters Radiation therapy tolerance limits: For one or for all?‐Janeway lecture , 1996, Cancer.

[56]  R. Weichselbaum,et al.  Expression of the polymorphic human DNA repair gene XRCC1 does not correlate with radiosensitivity in the cells of human head and neck tumor cell lines. , 1992, Radiation research.

[57]  J Isola,et al.  Distinct somatic genetic changes associated with tumor progression in carriers of BRCA1 and BRCA2 germ-line mutations. , 1997, Cancer research.

[58]  D. Murray,et al.  The importance of the ERCC1/ERCC4[XPF] complex for hypoxic-cell radioresistance does not appear to derive from its participation in the nucleotide excision repair pathway. , 1996, Mutation research.

[59]  H. Thames,et al.  Hyperfractionated radiotherapy of human tumors: overview of the randomized clinical trials. , 1997, International journal of radiation oncology, biology, physics.

[60]  S. Sawada,et al.  Radiation-induced apoptosis and necrosis in Molt-4 cells: a study of dose-effect relationships and their modification. , 1993, International journal of radiation biology.

[61]  John Calvin Reed Regulation of apoptosis by bcl-2 family proteins and its role in cancer and chemoresistance. , 1995, Current opinion in oncology.

[62]  L. Hartwell,et al.  The RAD9 gene controls the cell cycle response to DNA damage in Saccharomyces cerevisiae. , 1988, Science.

[63]  E. Sausville,et al.  UCN-01: a potent abrogator of G2 checkpoint function in cancer cells with disrupted p53. , 1996, Journal of the National Cancer Institute.

[64]  T. Wheldon,et al.  The effect of irradiation on function in self-renewing normal tissues with differing proliferative organisation. , 1982, The British journal of radiology.

[65]  J. Michaeli,et al.  Protein kinase C mediates basic fibroblast growth factor protection of endothelial cells against radiation-induced apoptosis. , 1994, Cancer research.

[66]  C. Ling,et al.  Synergistic effect of the v-myc oncogene with H-ras on radioresistance. , 1990, Cancer research.

[67]  A. Klippel,et al.  Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt , 1997, Molecular and cellular biology.

[68]  P. Thong,et al.  Sequestration of mitotic (M‐phase) chromosomes in autophagosomes: Mitotic programmed cell death in human Chang liver cells induced by an OH* burst from vanadyl(4) , 1996, The Anatomical record.

[69]  M. Karin,et al.  Three distinct signalling responses by murine fibroblasts to genotoxic stress , 1996, Nature.

[70]  Marlys Witte,et al.  Scatter factor promotes motility of human glioma and neuromicrovascular endothelial cells , 1998, International journal of cancer.

[71]  D. Brachman,et al.  Cellular and molecular mechanisms of radioresistance. , 1995, Cancer treatment and research.

[72]  Y. Shiloh,et al.  Predominance of null mutations in ataxia-telangiectasia. , 1996, Human molecular genetics.

[73]  J. Abrams,et al.  Role of interleukin 6 (IL-6) in protection from lethal irradiation and in endocrine responses to IL-1 and tumor necrosis factor , 1992, The Journal of experimental medicine.

[74]  H. Suit Assessment of the impact of local control on clinical outcome. , 1996, Frontiers of radiation therapy and oncology.

[75]  R. Cowan,et al.  Abnormal radiosensitivity of lymphocytes from breast cancer patients with excessive normal tissue damage after radiotherapy: chromosome aberrations after low dose-rate irradiation. , 1995, International journal of radiation biology.

[76]  A. Markoe,et al.  Radioresistance in murine solid tumors induced by interleukin-1. , 1996, Radiation research.

[77]  R. Muschel,et al.  The farnesyltransferase inhibitor FTI-277 radiosensitizes H-ras-transformed rat embryo fibroblasts. , 1996, Cancer research.

[78]  Yonghong Xiao,et al.  Association of BRCA1 with Rad51 in Mitotic and Meiotic Cells , 1997, Cell.

[79]  B. Vogelstein,et al.  A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia , 1992, Cell.

[80]  D. Hallahan,et al.  The interaction between recombinant human tumor necrosis factor and radiation in 13 human tumor cell lines. , 1990, International journal of radiation oncology, biology, physics.

[81]  G. Birrell,et al.  Normal tissue radiosensitivity in breast cancer patients. , 1995, International journal of radiation oncology, biology, physics.

[82]  Amanda G Paulovich,et al.  When Checkpoints Fail , 1997, Cell.

[83]  Steven E. Bayer,et al.  A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. , 1994, Science.

[84]  C. S. Freitas,et al.  Interleukin-1 and tumor necrosis factor-alpha as radio- and chemoprotectors of bone marrow. , 1993, Bone marrow transplantation.

[85]  S. Roberts,et al.  Chromosomal radiosensitivity in G2-phase lymphocytes as an indicator of cancer predisposition. , 1996, Radiation research.

[86]  David Baltimore,et al.  An Essential Role for NF-κB in Preventing TNF-α-Induced Cell Death , 1996, Science.

[87]  D. Baltimore,et al.  Dual roles of ATM in the cellular response to radiation and in cell growth control. , 1996, Genes & development.

[88]  C. Dinarello,et al.  Biologic basis for interleukin-1 in disease. , 1996, Blood.

[89]  M N Pollak,et al.  Influence of BRCA1 mutations on nuclear grade and estrogen receptor status of breast carcinoma in Ashkenazi Jewish women , 1997, Cancer.

[90]  F. Collins,et al.  The complete sequence of the coding region of the ATM gene reveals similarity to cell cycle regulators in different species. , 1995, Human molecular genetics.

[91]  L. Chodosh,et al.  Brca2 is coordinately regulated with Brca1 during proliferation and differentiation in mammary epithelial cells. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[92]  H. Withers,et al.  Late radiation response of kidney assayed by tubule-cell survival. , 1986, The British journal of radiology.

[93]  J C Reed,et al.  Somatic Frameshift Mutations in the BAX Gene in Colon Cancers of the Microsatellite Mutator Phenotype , 1997, Science.

[94]  Eugene V. Koonin,et al.  …Functional motifs… , 1996, Nature Genetics.

[95]  D. Thorley-Lawson,et al.  A novel form of Epstein-Barr virus latency in normal B cells in vivo , 1995, Cell.

[96]  G. Eichele,et al.  Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2 , 1997, Nature.

[97]  J. Kajstura,et al.  The insulin-like growth factor I receptor protects tumor cells from apoptosis in vivo. , 1995, Cancer research.

[98]  P. O'Connor,et al.  Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. , 1994, Science.

[99]  J. L. Roti,et al.  DNA supercoiling changes and nuclear matrix-associated proteins: possible role in oncogene-mediated radioresistance. , 1996, International journal of radiation oncology, biology, physics.

[100]  G. Evan,et al.  c‐Myc‐induced apoptosis in fibroblasts is inhibited by specific cytokines. , 1994, The EMBO journal.

[101]  A. Bardelli,et al.  HGF receptor associates with the anti‐apoptotic protein BAG‐1 and prevents cell death. , 1996, The EMBO journal.

[102]  J. Dunst,et al.  [Can an extremely elevated radiosensitivity in patients be recognized by the in-vitro testing of lymphocytes?]. , 1995, Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al].

[103]  D A Pierce,et al.  Studies of the mortality of atomic bomb survivors. Report 12, Part I. Cancer: 1950-1990. , 1996, Radiation research.

[104]  R. Weichselbaum,et al.  Loss of ceramide production confers resistance to radiation-induced apoptosis. , 1997, Cancer research.

[105]  B. Dörken,et al.  Expression of the bcl‐2 gene family in normal and malignant breast tissue: Low bax‐α expression in tumor cells correlates with resistance towards apoptosis , 1995, International journal of cancer.

[106]  A. Joseph,et al.  Scatter factor protein levels in human breast cancers: clinicopathological and biological correlations. , 1996, The American journal of pathology.

[107]  S. Hellman,et al.  Stem cell depletion: an explanation of the late effects of cytotoxins. , 1977, International journal of radiation oncology, biology, physics.

[108]  Junying Yuan,et al.  Functional role of interleukin 1 beta (IL-1 beta) in IL-1 beta- converting enzyme-mediated apoptosis , 1996, The Journal of experimental medicine.

[109]  G. Evan,et al.  Identification of domains of the insulin-like growth factor I receptor that are required for protection from apoptosis , 1997, Molecular and cellular biology.

[110]  V. Dixit,et al.  Type I Insulin-like Growth Factor Receptor Activation Regulates Apoptotic Proteins* , 1996, The Journal of Biological Chemistry.

[111]  A. Levine p53, the Cellular Gatekeeper for Growth and Division , 1997, Cell.

[112]  M. Ogawa,et al.  Immunoreactive hepatocyte growth factor is a strong and independent predictor of recurrence and survival in human breast cancer. , 1994, Cancer research.

[113]  J. Greenberger,et al.  Effects of recombinant cytokines on colony formation by irradiated human cord blood CD34+ hematopoietic progenitor cells. , 1997, Radiation research.

[114]  C. Land Studies of cancer and radiation dose among atomic bomb survivors. The example of breast cancer. , 1995, JAMA.

[115]  Y. Shiloh,et al.  Fragments of ATM which have dominant-negative or complementing activity , 1997, Molecular and cellular biology.

[116]  M. Lovett,et al.  A single ataxia telangiectasia gene with a product similar to PI-3 kinase. , 1995, Science.

[117]  S. Sukumar,et al.  Mutations in p53 as potential molecular markers for human breast cancer. , 1991, Proceedings of the National Academy of Sciences of the United States of America.