Advertisement

Cell Cycle Effects in Radiation Oncology

  • Randi G. SyljuåsenEmail author
Living reference work entry

Abstract

Cells in the human body can be either dividing or nondividing. In order to undergo cell division, the cycling cells sequentially enter four different cell cycle phases: G1, S, G2, and M. It has long been known that cells in different cell cycle phases display different radiosensitivity. Cells in late S phase are usually most radioresistant and cells in M phase most radiosensitive. One of the classical four “R”s describing the rationale behind fractionated radiotherapy is based on such cell cycle differences, as fractionation allows tumor cells in a radioresistant cell cycle phase to “Redistribute” into more radiosensitive phases before the next fractions. Furthermore, some chemotherapeutic or targeted drugs applied in combination with radiation therapy can cause the tumor cells to accumulate in radioresistant or radiosensitive cell cycle phases, thereby altering the tumor radiosensitivity. It is also well known that radiation halts cell cycle progression through inducing arrest at the cell cycle checkpoints. Three major radiation-induced cell cycle checkpoints exist, in G1, S, and G2 phase. Because most irradiated tumor cells do not die before attempting to divide, the checkpoints are important to allow time for repair of the radiation damage. The G1 checkpoint is dependent on the tumor suppressor p53 and is often deficient or lacking in tumor cells. Tumor cells may therefore rely more on the S and G2 checkpoints for repair of radiation damage compared to normal cells. One strategy for obtaining tumor selective radiosensitization is thus to combine radiation with drugs that abrogate the G2 checkpoint.

Keywords

Cell cycle checkpoints Radiosensitivity Cell cycle phase Checkpoint kinases ATR, Chk1 and Wee1 

References

  1. Beck H, Nahse-Kumpf V, Larsen MS, O'Hanlon KA, Patzke S, Holmberg C, Mejlvang J, Groth A, Nielsen O, Syljuåsen RG, Sørensen CS. Cyclin-dependent kinase suppression by WEE1 kinase protects the genome through control of replication initiation and nucleotide consumption. Mol Cell Biol. 2012;32(20):4226–36.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Brown JM, Attardi LD. The role of apoptosis in cancer development and treatment response. Nat Rev Cancer. 2005;5(3):231–7.PubMedCrossRefGoogle Scholar
  3. Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T, Hannon GJ. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature. 1995;377(6549):552–7.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Busse PM, Bose SK, Jones RW, Tolmach LJ. The action of caffeine on X-irradiated HeLa cells. II. Synergistic lethality. Radiat Res. 1977;71(3):666–77.PubMedCrossRefGoogle Scholar
  5. Cliby WA, Roberts CJ, Cimprich KA, Stringer CM, Lamb JR, Schreiber SL, Friend SH. Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints. EMBO J. 1998;17(1):159–69.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Di Leonardo A, Linke SP, Clarkin K, Wahl GM. DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev. 1994;8(21):2540–51.PubMedCrossRefGoogle Scholar
  7. Dillon MT, Bergerhoff KF, Pedersen M, Patin EC, Whittock H, Crespo-Rodriguez E, Pearson A, Paget JT, Smith HG, Patel RR, Foo S, Bozhanova G, Ragulan C, Fontana E, Desai K, Wilkins AC, Sadanandam A, Melcher A, McLaughlin M, Harrington KJ. ATR inhibition potentiates the radiation induced inflammatory tumour microenvironment. Clin Cancer Res. 2019;25(11):3392–403.PubMedCrossRefGoogle Scholar
  8. Dixon H, Norbury CJ. Therapeutic exploitation of checkpoint defects in cancer cells lacking p53 function. Cell Cycle. 2002;1(6):362–8.PubMedCrossRefGoogle Scholar
  9. Forrester HB, Vidair CA, Albright N, Ling CC, Dewey WC. Using computerized video time lapse for quantifying cell death of X-irradiated rat embryo cells transfected with c-myc or c-Ha-ras. Cancer Res. 1999;59(4):931–9.PubMedGoogle Scholar
  10. Hall EJ, Giaccia AJ. Radiobiology for the radiologist. Philadelphia: Lippincotts Williams & Wilkins; 2006.Google Scholar
  11. Hustedt N, Durocher D. The control of DNA repair by the cell cycle. Nat Cell Biol. 2016;19(1):1–9.PubMedCrossRefGoogle Scholar
  12. Iliakis G, Wang Y, Guan J, Wang H. DNA damage checkpoint control in cells exposed to ionizing radiation. Oncogene. 2003;22(37):5834–47.PubMedCrossRefGoogle Scholar
  13. Iliakis G, Wang H, Perrault AR, Boecker W, Rosidi B, Windhofer F, Wu W, Guan J, Terzoudi G, Pantelias G. Mechanisms of DNA double strand break repair and chromosome aberration formation. Cytogenet Genome Res. 2004;104(1–4):14–20.PubMedCrossRefGoogle Scholar
  14. Jeggo PA, Geuting V, Lobrich M. The role of homologous recombination in radiation-induced double-strand break repair. Radiother Oncol. 2011;101(1):7–12.PubMedCrossRefGoogle Scholar
  15. Li C, Nagasawa H, Tsang N, Little J. Radiation-induced irreversible g(0) g(1) block is abolished in human-diploid fibroblasts transfected with the human papilloma-virus e6 gene – implication of the p53-cip1 waf1 pathway. Int J Oncol. 1995;6(1):233–6.PubMedGoogle Scholar
  16. Linke SP, Clarkin KC, Wahl GM. p53 mediates permanent arrest over multiple cell cycles in response to gamma-irradiation. Cancer Res. 1997;57(6):1171–9.PubMedGoogle Scholar
  17. Liu Q, Guntuku S, Cui XS, Matsuoka S, Cortez D, Tamai K, Luo G, Carattini-Rivera S, DeMayo F, Bradley A, Donehower LA, Elledge SJ. Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes Dev. 2000;14(12):1448–59.PubMedPubMedCentralGoogle Scholar
  18. Lund-Andersen C, Patzke S, Nahse-Kumpf V, Syljuåsen RG. PLK1-inhibition can cause radiosensitization or radioresistance dependent on the treatment schedule. Radiother Oncol. 2014;110(2):355–61.PubMedCrossRefGoogle Scholar
  19. Ma CX, Janetka JW, Piwnica-Worms H. Death by releasing the breaks: CHK1 inhibitors as cancer therapeutics. Trends Mol Med. 2011;17(2):88–96.PubMedCrossRefGoogle Scholar
  20. Milas L, Milas MM, Mason KA. Combination of taxanes with radiation: preclinical studies. Semin Radiat Oncol. 1999;9(2 Suppl 1):12–26.PubMedGoogle Scholar
  21. Nagasawa H, Keng P, Maki C, Yu Y, Little JB. Absence of a radiation-induced first-cycle G1-S arrest in p53+ human tumor cells synchronized by mitotic selection. Cancer Res. 1998;58(9):2036–41.PubMedGoogle Scholar
  22. Pawlik TM, Keyomarsi K. Role of cell cycle in mediating sensitivity to radiotherapy. Int J Radiat Oncol Biol Phys. 2004;59(4):928–42.PubMedCrossRefGoogle Scholar
  23. Pilie PG, Tang C, Mills GB, Yap TA. State-of-the-art strategies for targeting the DNA damage response in cancer. Nat Rev Clin Oncol. 2019;16(2):81–104.PubMedCrossRefGoogle Scholar
  24. Russell KJ, Wiens LW, Demers GW, Galloway DA, Plon SE, Groudine M. Abrogation of the G2 checkpoint results in differential radiosensitization of G1 checkpoint-deficient and G1 checkpoint-competent cells. Cancer Res. 1995;55(8):1639–42.PubMedGoogle Scholar
  25. Sanchez Y, Wong C, Thoma RS, Richman R, Wu Z, Piwnica-Worms H, Elledge SJ. Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25. Science. 1997;277(5331):1497–501.PubMedCrossRefGoogle Scholar
  26. Sinclair WK. Cyclic x-ray responses in mammalian cells in vitro. Radiat Res. 1968;33(3):620–43.PubMedCrossRefGoogle Scholar
  27. Sørensen CS, Syljuåsen RG, Falck J, Schroeder T, Ronnstrand L, Khanna KK, Zhou BB, Bartek J, Lukas J. Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A. Cancer Cell. 2003;3(3):247–58.PubMedCrossRefGoogle Scholar
  28. Syljuåsen RG, Krolewski B, Little JB. Loss of normal G1 checkpoint control is an early step in carcinogenesis, independent of p53 status. Cancer Res. 1999;59(5):1008–14.PubMedGoogle Scholar
  29. Syljuåsen RG, Sørensen CS, Nylandsted J, Lukas C, Lukas J, Bartek J. Inhibition of Chk1 by CEP-3891 accelerates mitotic nuclear fragmentation in response to ionizing radiation. Cancer Res. 2004;64(24):9035–40.PubMedCrossRefGoogle Scholar
  30. Syljuåsen RG, Hasvold G, Hauge S, Helland A. Targeting lung cancer through inhibition of checkpoint kinases. Front Genet. 2015;6:70.PubMedPubMedCentralGoogle Scholar
  31. Tamulevicius P, Wang M, Iliakis G. Homology-directed repair is required for the development of radioresistance during S phase: interplay between double-strand break repair and checkpoint response. Radiat Res. 2007;167(1):1–11.PubMedCrossRefGoogle Scholar
  32. Tsang NM, Nagasawa H, Li C, Little JB. Abrogation of p53 function by transfection of HPV16 E6 gene enhances the resistance of human diploid fibroblasts to ionizing radiation. Oncogene. 1995;10(12):2403–8.PubMedGoogle Scholar
  33. Vendetti FP, Karukonda P, Clump DA, Teo T, Lalonde R, Nugent K, Ballew M, Kiesel BF, Beumer JH, Sarkar SN, Conrads TP, O'Connor MJ, Ferris RL, Tran PT, Delgoffe GM, Bakkenist CJ. ATR kinase inhibitor AZD6738 potentiates CD8+ T cell-dependent antitumor activity following radiation. J Clin Invest. 2018;128(9):3926–40.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Wang Y, Li J, Booher RN, Kraker A, Lawrence T, Leopold WR, Sun Y. Radiosensitization of p53 mutant cells by PD0166285, a novel G(2) checkpoint abrogator. Cancer Res. 2001;61(22):8211–7.PubMedGoogle Scholar
  35. Wang X, Khadpe J, Hu B, Iliakis G, Wang Y. An overactivated ATR/CHK1 pathway is responsible for the prolonged G2 accumulation in irradiated AT cells. J Biol Chem. 2003;278(33):30869–74.PubMedCrossRefGoogle Scholar
  36. Wilson PF, Hinz JM, Urbin SS, Nham PB, Thompson LH. Influence of homologous recombinational repair on cell survival and chromosomal aberration induction during the cell cycle in gamma-irradiated CHO cells. DNA Repair (Amst). 2010;9(7):737–44.CrossRefGoogle Scholar
  37. Withers HR. Cell cycle redistribution as a factor in multifraction irradiation. Radiology. 1975a;114(1):199–202.PubMedCrossRefGoogle Scholar
  38. Withers HR. The four R’s of radiotherapy. Adv Radiat Biol. 1975b;5:241–71.CrossRefGoogle Scholar
  39. Wouters BG. Cell death after irradiation: how, when and why cells die. In: Joiner M, Van der Kogel A, editors. Basic clinical radiobiology 2009. London: Hodder Arnold; 2009. p. 23–40.Google Scholar
  40. Xu B, Kim ST, Lim DS, Kastan MB. Two molecularly distinct G(2)/M checkpoints are induced by ionizing irradiation. Mol Cell Biol. 2002;22(4):1049–59.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Zhao H, Piwnica-Worms H. ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1. Mol Cell Biol. 2001;21(13):4129–39.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium HospitalOslo University HospitalOsloNorway

Personalised recommendations