Skip to main content
SpringerLink
Log in

Overview of Cancer Molecular Radiobiology

  • Chapter
Radiation Oncology Advances

Part of the book series: Cancer Treatment and Research ((CTAR,volume 139))

The first recorded use of X-rays for the treatment of cancer occurred within about 1 year of their discovery in the late 1800s by Roentgen. The study of X-rays and other ionizing radiations, and their clinical application to cancer treatment, has become increasingly sophisticated. This chapter will provide an overview of the molecular responses induced in cells by ionizing radiation and will discuss how molecularly targeted inhibitors can be used to enhance the efficacy of therapeutic radiation.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ward JF. The complexity of DNA damage: relevance to biological consequences. Int J Radiat Biol 1994; 66(5):427–432.

    Article  CAS  PubMed  Google Scholar 

  2. Hartwell LH, Kastan MB. Cell cycle control and cancer. Science 1994; 266(5192):1821–1828.

    Article  CAS  PubMed  Google Scholar 

  3. Lukas J, Lukas C, Bartek J. Mammalian cell cycle checkpoints: signalling pathways and their organization in space and time. DNA Repair (Amst) 2004; 3(8–9):997–1007.

    Article  CAS  Google Scholar 

  4. Bradshaw PS, Stavropoulos DJ, Meyn MS. Human telomeric protein TRF2 associates with genomic double-strand breaks as an early response to DNA damage. Nat Genet 2005; 37(2):193–197.

    Article  CAS  PubMed  Google Scholar 

  5. Bristow RG, Harrington L. Genetic Instability and DNA Repair; Chapter 5. In: Tannock IF HR, Harrington L and Bristow RG, ed. The Basic Science of Oncology. 4th ed. New York: McGraw-Hill Ltd.; 2005:77–99.

    Google Scholar 

  6. Choudhury A, Cuddihy A, Bristow R. Radiation and Other New Molecular-Targeted Agents, Part I: Targeting ATM-p53, ATR-CHK1, DNA Repair and the Proteasome. Semin Radiat Oncol2006; 16:51–58.

    Google Scholar 

  7. Valerie K, Povirk LF. Regulation and mechanisms of mammalian double-strand break repair. Oncogene 2003; 22(37):5792–5812.

    Article  CAS  PubMed  Google Scholar 

  8. Powell SN, Kachnic LA. Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation. Oncogene 2003; 22(37):5784–5791.

    Article  CAS  PubMed  Google Scholar 

  9. Jeggo PA. The fidelity of repair of radiation damage. Radiat Prot Dosimetry 2002; 99(1–4):117–122.

    CAS  PubMed  Google Scholar 

  10. Kitada S, Krajewski S, Miyashita T, Krajewska M, Reed JC. Gamma-radiation induces upregulation of Bax protein and apoptosis in radiosensitive cells in vivo. Oncogene 1996; 12(1):187–192.

    CAS  PubMed  Google Scholar 

  11. Kolesnick R, Fuks Z. Radiation and ceramide-induced apoptosis. Oncogene 2003; 22(37):5897–5906.

    Article  CAS  PubMed  Google Scholar 

  12. Ruiter GA, Zerp SF, Bartelink H, van Blitterswijk WJ, Verheij M. Alkyl-lysophospholipids activate the SAPK/JNK pathway and enhance radiation-induced apoptosis. Cancer Res 1999; 59(10):2457–2463.

    CAS  PubMed  Google Scholar 

  13. Paris F, Fuks Z, Kang A, et al. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science 2001; 293(5528):293–297.

    Article  CAS  PubMed  Google Scholar 

  14. Kasid U, Suy S, Dent P, Ray S, Whiteside TL, Sturgill TW. Activation of Raf by ionizing radiation. Nature 1996; 382(6594):813–816.

    Article  CAS  PubMed  Google Scholar 

  15. Gupta AK, Bakanauskas VJ, Cerniglia GJ, et al. The Ras radiation resistance pathway. Cancer Res 2001; 61(10):4278–4282.

    CAS  PubMed  Google Scholar 

  16. Kasid U, Dritschilo A. RAF antisense oligonucleotide as a tumor radiosensitizer. Oncogene 2003; 22(37):5876–5884.

    Article  CAS  PubMed  Google Scholar 

  17. McKenna WG, Weiss MC, Endlich B, et al. Synergistic effect of the v-myc oncogene with H-ras on radioresistance. Cancer Res 1990; 50(1):97–102.

    CAS  PubMed  Google Scholar 

  18. Bristow RG, Benchimol S, Hill RP. The p53 gene as a modifier of intrinsic radiosensitivity: implications for radiotherapy. Radiother Oncol 1996; 40(3):197–223.

    Article  CAS  PubMed  Google Scholar 

  19. Hahn SM, Bernhard EJ, Regine W, et al. A Phase I trial of the farnesyltransferase inhibitor L-778, 123 and radiotherapy for locally advanced lung and head and neck cancer. Clin Cancer Res 2002; 8(5):1065–1072.

    CAS  PubMed  Google Scholar 

  20. Nakamura S, Watanabe H, Miura M, Sasaki T. Effect of the insulin-like growth factor I receptor on ionizing radiation-induced cell death in mouse embryo fibroblasts. Exp Cell Res 1997; 235(1):287–294.

    Article  CAS  PubMed  Google Scholar 

  21. Perer ES, Madan AK, Shurin A, et al. Insulin-like growth factor I receptor antagonism augments response to chemoradiation therapy in colon cancer cells. J Surg Res 2000; 94(1):1–5.

    Article  CAS  PubMed  Google Scholar 

  22. Macaulay VM, Salisbury AJ, Bohula EA, Playford MP, Smorodinsky NI, Shiloh Y. Downregulation of the type 1 insulin-like growth factor receptor in mouse melanoma cells is associated with enhanced radiosensitivity and impaired activation of Atm kinase. Oncogene 2001; 20(30):4029–4040.

    Article  CAS  PubMed  Google Scholar 

  23. Allen GA, Armstrong E, Modhia F, Ludwig DL, Hicklin DJ, Harari PM. Inhibition of insulin-like growth factor-1 receptor signaling impairs proliferation of head and neck, lung, prostate and breast cancer cells. In: American Association of Cancer Research; 2005 April 9, 2005; Anaheim, CA; 2005.

    Google Scholar 

  24. Wen B, Deutsch E, Marangoni E, et al. Tyrphostin AG 1024 modulates radiosensitivity in human breast cancer cells. Br J Cancer 2001; 85(12):2017–2021.

    Article  CAS  PubMed  Google Scholar 

  25. Saucedo LJ, Gao X, Chiarelli DA, Li L, Pan D, Edgar BA. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nature Cell Biol 2003; 5(6):566–571 [erratum appears in Nat Cell Biol. 2003 Jul; 5(7):680].

    Google Scholar 

  26. Castro AF, Rebhun JF, Clark GJ, Quilliam LA. Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner. J Biol Chem 2003; 278(35):32493–32496.

    Article  CAS  PubMed  Google Scholar 

  27. Garami A, Zwartkruis FJ, Nobukuni T, et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell 2003; 11(6):1457–1466.

    Article  CAS  PubMed  Google Scholar 

  28. Inoki K, Li Y, Xu T, Guan K-L. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 2003; 17(15):1829–1834.

    Article  CAS  PubMed  Google Scholar 

  29. Shaw RJ, Bardeesy N, Manning BD, et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 2004; 6(1):91–99.

    Article  CAS  PubMed  Google Scholar 

  30. Corradetti MN, Inoki K, Bardeesy N, DePinho RA, Guan KL. Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz–Jeghers syndrome. Genes Dev 2004; 18(13):1533–1538.

    Article  CAS  PubMed  Google Scholar 

  31. Shi Y, Frankel A, Radvanyi LG, Penn LZ, Miller RG, Mills GB. Rapamycin enhances apoptosis and increases sensitivity to cisplatin in vitro. Cancer Res 1995; 55(9):1982–1988.

    CAS  PubMed  Google Scholar 

  32. Wan X, Helman LJ. Effect of insulin-like growth factor II on protecting myoblast cells against cisplatin-induced apoptosis through p70 S6 kinase pathway. Neoplasia (New York) 2002; 4(5):400–408.

    CAS  Google Scholar 

  33. Geoerger B, Kerr K, Tang C-B, et al. Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy. Cancer Res 2001; 61(4):1527–1532.

    CAS  PubMed  Google Scholar 

  34. Beuvink I, Boulay A, Fumagalli S, et al. The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell 2005; 120(6):747–759.

    Article  CAS  PubMed  Google Scholar 

  35. Fowler JF. Biological factors influencing optimum fractionation in radiation therapy. Acta Oncol 2001; 40(6):712–717.

    Article  CAS  PubMed  Google Scholar 

  36. Bentzen SM. Repopulation in radiation oncology: perspectives of clinical research. Int J Radiat Biol 2003; 79(7):581–585.

    Article  CAS  PubMed  Google Scholar 

  37. Eshleman JS, Carlson BL, Mladek AC, Kastner BD, Shide KL, Sarkaria JN. Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy. Cancer Res 2002; 62(24):7291–7297.

    CAS  PubMed  Google Scholar 

  38. Maloney A, Workman P. HSP90 as a new therapeutic target for cancer therapy: the story unfolds. Expert Opin Biol Ther 2002; 2(1):3–24.

    Article  CAS  PubMed  Google Scholar 

  39. Machida H, Matsumoto Y, Shirai M, Kubota N. Geldanamycin, an inhibitor of Hsp90, sensitizes human tumour cells to radiation. Int J Radiat Biol 2003; 79(12):973–980.

    Article  CAS  PubMed  Google Scholar 

  40. Russell JS, Burgan W, Oswald KA, Camphausen K, Tofilon PJ. Enhanced cell killing induced by the combination of radiation and the heat shock protein 90 inhibitor 17-allylamino-17- demethoxygeldanamycin: a multitarget approach to radiosensitization. Clin Cancer Res 2003; 9(10 Pt 1):3749–3755.

    Google Scholar 

  41. Bisht KS, Bradbury CM, Mattson D, et al. Geldanamycin and 17-allylamino-17-demethoxygeldanamycin potentiate the in vitro and in vivo radiation response of cervical tumor cells via the heat shock protein 90-mediated intracellular signaling and cytotoxicity. Cancer Res 2003; 63(24):8984–8995.

    CAS  PubMed  Google Scholar 

  42. Bull EE, Dote H, Brady KJ, et al. Enhanced tumor cell radiosensitivity and abrogation of G2 and S phase arrest by the Hsp90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin. Clin Cancer Res 2004; 10(23):8077–8084.

    Article  CAS  PubMed  Google Scholar 

  43. Enmon R, Yang WH, Ballangrud AM, et al. Combination treatment with 17-N-allylamino-17-demethoxy geldanamycin and acute irradiation produces supra-additive growth suppression in human prostate carcinoma spheroids. Cancer Res 2003; 63(23):8393–8399.

    CAS  PubMed  Google Scholar 

  44. Zhu A, Shaeffer J, Leslie S, Kolm P, El-Mahdi AM. Epidermal growth factor receptor: an independent predictor of survival in astrocytic tumors given definitive irradiation. Int J Radiat Oncol Biol Phys 1996; 34(4):809–815.

    CAS  PubMed  Google Scholar 

  45. Sheridan MT, O’Dwyer T, Seymour CB, Mothersill CE. Potential indicators of radiosensitivity in squamous cell carcinoma of the head and neck. Radiat Oncol Invest 1997; 5(4):180–186.

    Article  CAS  Google Scholar 

  46. Milas L, Fan Z, Andratschke NH, Ang KK. Epidermal growth factor receptor and tumor response to radiation: in vivo preclinical studies. Int J Radiat Oncol Biol Phys 2004; 58(3):966–971.

    CAS  PubMed  Google Scholar 

  47. Huang SM, Bock JM, Harari PM. Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res 1999; 59(8):1935–1940.

    CAS  PubMed  Google Scholar 

  48. Bianco C, Tortora G, Bianco R, et al. Enhancement of antitumor activity of ionizing radiation by combined treatment with the selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 (Iressa). Clin Cancer Res 2002; 8(10):3250–3258.

    CAS  PubMed  Google Scholar 

  49. Agus DB, Scher HI, Higgins B, et al. Response of prostate cancer to anti-Her-2/neu antibody in androgen-dependent and -independent human xenograft models. Cancer Res 1999; 59(19):4761–4764.

    CAS  PubMed  Google Scholar 

  50. Grana TM, Rusyn EV, Zhou H, Sartor CI, Cox AD. Ras mediates radioresistance through both phosphatidylinositol 3-kinase-dependent and Raf-dependent but mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-independent signaling pathways. Cancer Res 2002; 62(14):4142–4150.

    CAS  PubMed  Google Scholar 

  51. Kennedy SG, Wagner AJ, Conzen SD, et al. The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Genes Dev 1997; 11(6):701–713.

    Article  CAS  PubMed  Google Scholar 

  52. Vanhaesebroeck B, Leevers SJ, Panayotou G, Waterfield MD. Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends Biochem Sci 1997; 22(7):267–272.

    Article  CAS  PubMed  Google Scholar 

  53. McKenna WG, Muschel RJ, Gupta AK, Hahn SM, Bernhard EJ. The RAS signal transduction pathway and its role in radiation sensitivity. Oncogene 2003; 22(37):5866–5875.

    Article  CAS  PubMed  Google Scholar 

  54. Gupta AK, Cerniglia GJ, Mick R, et al. Radiation sensitization of human cancer cells in vivo by inhibiting the activity of PI3K using LY294002. Int J Radiat Oncol Biol Phys 2003; 56(3):846–853.

    CAS  PubMed  Google Scholar 

  55. Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK. Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 2001; 1(3):194–202.

    Article  CAS  PubMed  Google Scholar 

  56. Marshall JL, Rizvi N, Kauh J, et al. A phase I trial of depsipeptide (FR901228) in patients with advanced cancer. J Exp Ther Oncol 2002; 2(6):325–332.

    Article  CAS  PubMed  Google Scholar 

  57. Kelly WK, Richon VM, O’Connor O, et al. Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clin Cancer Res 2003; 9(10 Pt 1): 3578–3588.

    Google Scholar 

  58. Johnstone RW. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov 2002; 1(4):287–299.

    Article  CAS  PubMed  Google Scholar 

  59. Chinnaiyan P, Allen G, Harari PM. Radiation and new molecular agents, Part II: Targeting HDAC, HSP90, IGF-1R, PI3K and Ras. Semin Radiat Oncol 2006; 16:59–65.

    Article  PubMed  Google Scholar 

  60. Ljungman M. The influence of chromatin structure on the frequency of radiation-induced DNA strand breaks: a study using nuclear and nucleoid monolayers. Radiat Res 1991; 126(1):58–64.

    Article  CAS  PubMed  Google Scholar 

  61. Nackerdien Z, Michie J, Bohm L. Chromatin decondensed by acetylation shows an elevated radiation response. Radiat Res 1989; 117(2):234–244.

    Article  CAS  PubMed  Google Scholar 

  62. Warters RL, Childers TJ. Radiation-induced thymine base damage in replicating chromatin. Radiat Res 1982; 90(3):564–574.

    Article  CAS  PubMed  Google Scholar 

  63. Camphausen K, Scott T, Sproull M, Tofilon PJ. Enhancement of xenograft tumor radiosensitivity by the histone deacetylase inhibitor MS-275 and correlation with histone hyperacetylation. Clin Cancer Res 2004; 10(18 Pt 1):6066–6071.

    Google Scholar 

  64. Chinnaiyan P, Valabhaneni G, Armstrong E, Huang S, Harari PM. Modulating radiation response with the histone deacetylase (HDAC) inhibitor SAHA in human carcinomas. Int J Radiat Oncol Biol Phys 2005; 62(1):223–229.

    Article  CAS  PubMed  Google Scholar 

  65. Fuino L, Bali P, Wittmann S, et al. Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. Mol Cancer Ther 2003; 2(10):971–984.

    CAS  PubMed  Google Scholar 

  66. Yu X, Guo ZS, Marcu MG, et al. Modulation of p53, ErbB1, ErbB2, and Raf-1 expression in lung cancer cells by depsipeptide FR901228. J Natl Cancer Inst 2002; 94(7):504–513.

    CAS  PubMed  Google Scholar 

  67. Lippman ME, Benz C, Chinnaiyan A, et al. Consensus statement: expedition inspiration 2004 Breast Cancer Symposium ‘Breast Cancer–the Development and Validation of New Therapeutics’. Breast Cancer Res Treat 2005; 90(1):1–3.

    Article  PubMed  Google Scholar 

  68. Camphausen K, Burgan W, Cerra M, et al. Enhanced radiation-induced cell killing and prolongation of gammaH2AX foci expression by the histone deacetylase inhibitor MS-275. Cancer Res 2004; 64(1):316–321.

    Article  CAS  PubMed  Google Scholar 

  69. Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem 1998; 273(10):5858–5868.

    Article  CAS  PubMed  Google Scholar 

  70. Nazarov IB, Smirnova AN, Krutilina RI, et al. Dephosphorylation of histone gamma-H2AX during repair of DNA double-strand breaks in mammalian cells and its inhibition by calyculin A. Radiat Res 2003; 160(3):309–317.

    Article  CAS  PubMed  Google Scholar 

  71. Rothkamm K, Kruger I, Thompson LH, Lobrich M. Pathways of DNA double-strand break repair during the mammalian cell cycle. Mol Cell Biol 2003; 23(16):5706–5715.

    Article  CAS  PubMed  Google Scholar 

  72. McBride WH, Iwamoto KS, Syljuasen R, Pervan M, Pajonk F. The role of the ubiquitin/proteasome system in cellular responses to radiation. Oncogene 2003; 22(37):5755–5773.

    Article  CAS  PubMed  Google Scholar 

  73. Krogan NJ, Lam MH, Fillingham J, et al. Proteasome involvement in the repair of DNA double-strand breaks. Mol Cell 2004; 16(6):1027–1034.

    Article  CAS  PubMed  Google Scholar 

  74. Kurland JF, Meyn RE. Protease inhibitors restore radiation-induced apoptosis to Bcl-2-expressing lymphoma cells. Int J Cancer 2001; 96(6):327–333.

    Article  CAS  PubMed  Google Scholar 

  75. Teicher BA, Ara G, Herbst R, Palombella VJ, Adams J. The proteasome inhibitor PS-341 in cancer therapy. Clin Cancer Res 1999; 5(9):2638–2645.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA

    Jann N. Sarkaria M.D

  2. Department of Radiation Oncology, Princess Margaret Hospital – University Health Network, M5G 2M9, Toronto, ON, Canada

    Robert G. Bristow M.D., Ph.D

Authors
  1. Jann N. Sarkaria M.D
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert G. Bristow M.D., Ph.D
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue, K4/310, 53792, Madison, WI, USA

    Søren M. Bentzen Ph.D., D.Sc , Paul M. Harari M.D , Wolfgang A. Tomé M.D., Ph.D  & Minesh P. Mehta M.D , ,  & 

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Sarkaria, J.N., Bristow, R.G. (2008). Overview of Cancer Molecular Radiobiology. In: Bentzen, S.M., Harari, P.M., Tomé, W.A., Mehta, M.P. (eds) Radiation Oncology Advances. Cancer Treatment and Research, vol 139. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-36744-6_6

Download citation

  • DOI: https://doi.org/10.1007/978-0-387-36744-6_6

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-0-387-36743-9

  • Online ISBN: 978-0-387-36744-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation