Skip to main content
SpringerLink
Log in

Radiosensitisation by Poly(ADP-ribose) Polymerase Inhibition

  • Chapter
  • First Online:
PARP Inhibitors for Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D,volume 83))

  • 1665 Accesses

Abstract

Whilst the depletion of poly(ADP-ribose) polymerase (PARP) activity associated with PARP-1 and PARP-2 in cells causes radiosensitivity, its inhibition by small molecule inhibitors is showing great potential as a mechanism to potentiate the effects of radiotherapy. Indeed as over 50 % of all cancer patients will receive radiotherapy at some point in their treatment there is considerable interest in the development of radiosensitisers that can replace chemotherapeutic agents without the associated dose-limiting toxicities. Potent and specific inhibitors of PARP activity that compete with NAD+ at the enzyme’s activity site have been developed. Their use in preclinical in vitro and in vivo models is associated with enhanced radiosensitivity through mechanisms that not only involve the trapping of the PARP proteins at sites of strand breaks and the modulation of DNA repair in a proliferation dependent manner but also through the targeting of the endothelium and tumour vasculature and changes in tumour oxygenation and thus hypoxia-related radioresistance. However as both PARP-1 and PARP-2 are also involved in transcription regulation, chromatin modification and cellular homeostasis, the impact of PARP inhibition on these processes and long-term therapeutic responses needs to be investigated, as well as issues relating to scheduling, dose and radiation quality on the efficacy of this combined therapy.

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 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
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

References

  1. Chambon P, Weill J, Mandel P (1963) Nicotinamide mononucleotide activation of new DNA-dependent polyadenylic acid synthesizing nuclear enzyme. Biochem Biophys Res Commun 11:39–43

    CAS  PubMed  Google Scholar 

  2. Virág L, Szabó C (2002) The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev 54:375–429

    PubMed  Google Scholar 

  3. Schreiber V, Dantzer F, Ame J-C, de Murcia G (2006) Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol 7:517–528. doi:10.1038/nrm1963

    CAS  PubMed  Google Scholar 

  4. D’Amours D, Desnoyers S, D’Silva I, Poirier GG (1999) Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem J 342:249–268

    PubMed Central  PubMed  Google Scholar 

  5. El-Khamisy SF, Masutani M, Suzuki H, Caldecott KW (2003) A requirement for PARP-1 for the assembly or stability of XRCC1 nuclear foci at sites of oxidative DNA damage. Nucleic Acids Res 31:5526–5533. doi:10.1093/nar/gkg761

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Caldecott KW (2003) XRCC1 and DNA strand break repair. DNA Repair (Amst) 2:955–969. doi:10.1016/S1568-7864(03)00118-6

    CAS  Google Scholar 

  7. Durkacz B, Omidiji O, Gray D, Shall S (1980) (ADP-ribose) n participates in DNA excision repair. Nature 283:593–596

    CAS  PubMed  Google Scholar 

  8. Ben-Hur E, Chen C, Elkind M (1985) Inhibitors of poly (adenosine diphosphoribose) synthetase, examination of metabolic perturbations, and enhancement of radiation response in Chinese hamster cells. Cancer Res 45:2123–2127

    CAS  PubMed  Google Scholar 

  9. Powell C, Mikropoulos C, Kaye SB, Nutting CM, Bhide SA, Newbold K, Harrington KJ (2010) Pre-clinical and clinical evaluation of PARP inhibitors as tumour-specific radiosensitisers. Cancer Treat Rev 36:566–575. doi:10.1016/j.ctrv.2010.03.003

    CAS  PubMed  Google Scholar 

  10. Chalmers AJ, Lakshman M, Chan N, Bristow RG (2010) Poly(ADP-ribose) polymerase inhibition as a model for synthetic lethality in developing radiation oncology targets. Semin Radiat Oncol 20:274–281. doi:10.1016/j.semradonc.2010.06.001

    PubMed  Google Scholar 

  11. De Vos M, Schreiber V, Dantzer F (2012) The diverse roles and clinical relevance of PARPs in DNA damage repair: current state of the art. Biochem Pharmacol 84:137–146. doi:10.1016/j.bcp.2012.03.018

    CAS  PubMed  Google Scholar 

  12. De Murcia JM, Niedergang C, Trucco C, Ricoul M, Dutrillaux B, Mark M, Oliver FJ, Masson M, Dierich A, Lemeur M, Walztinger C, Chambon P, de Murcia G (1997) Requirement of poly (ADP-ribose) polymerase in recovery from DNA damage in mice and in cells Requirement of poly (ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc Natl Acad Sci U S A 94:7303–7307

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Wang Z, Stingl L, Morrison C, Jantsch M, Los M, Schulze-Osthoff K, Wagner EF (1997) PARP is important for genomic stability but dispensable in apoptosis. Genes Dev 11:2347–2358. doi:10.1101/gad.11.18.2347

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Meyer R, Müller M, Beneke S, Küpper JH, Bürkle A (2000) Negative regulation of alkylation-induced sister-chromatid exchange by poly(ADP-ribose) polymerase-1 activity. Int J Cancer 88:351–355

    CAS  PubMed  Google Scholar 

  15. Trucco C, Oliver FJ, de Murcia G, Ménissier-de Murcia J (1998) DNA repair defect in poly(ADP-ribose) polymerase-deficient cell lines. Nucleic Acids Res 26:2644–2649

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Godon C, Cordelières FP, Biard D, Giocanti N, Mégnin-Chanet F, Hall J, Favaudon V (2008) PARP inhibition versus PARP-1 silencing: different outcomes in terms of single-strand break repair and radiation susceptibility. Nucleic Acids Res 36:4454–4464. doi:10.1093/nar/gkn403

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Ding R, Pommier Y, Kang VH, Smulson M (1992) Depletion of poly(ADP-ribose) polymerase by antisense RNA expression results in a delay in DNA strand break rejoining. J Biol Chem 267:12804–12812

    CAS  PubMed  Google Scholar 

  18. Fisher AEO, Hochegger H, Takeda S, Caldecott KW (2007) Poly(ADP-ribose) polymerase 1 accelerates single-strand break repair in concert with poly(ADP-ribose) glycohydrolase. Mol Cell Biol 27:5597–5605. doi:10.1128/MCB.02248-06

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Ariumi Y, Masutani M, Copeland TD, Mimori T, Sugimura T, Shimotohno K, Ueda K, Hatanaka M, Noda M (1999) Suppression of the poly(ADP-ribose) polymerase activity by DNA-dependent protein kinase in vitro. Oncogene 18:4616–4625. doi:10.1038/sj.onc.1202823

    CAS  PubMed  Google Scholar 

  20. Galande S, Kohwi-Shigematsu T (1999) Poly(ADP-ribose) polymerase and Ku autoantigen form a complex and synergistically bind to matrix attachment sequences. J Biol Chem 274:20521–20528

    CAS  PubMed  Google Scholar 

  21. Haince J-F, Kozlov S, Dawson VL, Dawson TM, Hendzel MJ, Lavin MF, Poirier GG (2007) Ataxia telangiectasia mutated (ATM) signaling network is modulated by a novel poly(ADP-ribose)-dependent pathway in the early response to DNA-damaging agents. J Biol Chem 282:16441–16453. doi:10.1074/jbc.M608406200

    CAS  PubMed  Google Scholar 

  22. Haince J-F, McDonald D, Rodrigue A, Déry U, Masson J-Y, Hendzel MJ, Poirier GG (2008) PARP1-dependent kinetics of recruitment of MRE11 and NBS1 proteins to multiple DNA damage sites. J Biol Chem 283:1197–1208. doi:10.1074/jbc.M706734200

    CAS  PubMed  Google Scholar 

  23. Bryant HE, Petermann E, Schultz N, Jemth A-S, Loseva O, Issaeva N, Johansson F, Fernandez S, McGlynn P, Helleday T (2009) PARP is activated at stalled forks to mediate Mre11-dependent replication restart and recombination. EMBO J 28:2601–2615. doi:10.1038/emboj.2009.206

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Hochegger H, Dejsuphong D, Fukushima T, Morrison C, Sonoda E, Schreiber V, Zhao GY, Saberi A, Masutani M, Adachi N, Koyama H, de Murcia G, Takeda S (2006) PARP-1 protects homologous recombination from interference by Ku and Ligase IV in vertebrate cells. EMBO J 25:1305–1314. doi:10.1038/sj.emboj.7601015

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Schultz N, Lopez E, Saleh-Gohari N, Helleday T (2003) Poly(ADP-ribose) polymerase (PARP-1) has a controlling role in homologous recombination. Nucleic Acids Res 31:4959–4964. doi:10.1093/nar/gkg703

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Yang Y-G, Cortes U, Patnaik S, Jasin M, Wang Z-Q (2004) Ablation of PARP-1 does not interfere with the repair of DNA double-strand breaks, but compromises the reactivation of stalled replication forks. Oncogene 23:3872–3882. doi:10.1038/sj.onc.1207491

    CAS  PubMed  Google Scholar 

  27. Adamson B, Smogorzewska A, Sigoillot F, King R, Elledge SJ (2012) A genome-wide homologous recombination screen identifies the RNA-binding protein RBMX as a component of the DNA-damage response. Nat Cell Biol 14:318–328. doi:10.1038/ncb2426.A

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Noël G, Giocanti N, Fernet M, Mégnin-Chanet F, Favaudon V (2003) Poly(ADP-ribose) polymerase (PARP-1) is not involved in DNA double-strand break recovery. BMC Cell Biol 4:7. doi:10.1186/1471-2121-4-7

    PubMed Central  PubMed  Google Scholar 

  29. Ruscetti T, Lehnert BE, Halbrook J, Le Trong H, Hoekstra MF, Chen DJ, Peterson SR (1998) Stimulation of the DNA-dependent protein kinase by poly(ADP-ribose) polymerase. J Biol Chem 273:14461–14467

    CAS  PubMed  Google Scholar 

  30. Spagnolo L, Barbeau J, Curtin NJ, Morris EP, Pearl LH (2012) Visualization of a DNA-PK/PARP1 complex. Nucleic Acids Res 40:4168–4177. doi:10.1093/nar/gkr1231

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Audebert M, Salles B, Calsou P (2004) Involvement of poly(ADP-ribose) polymerase-1 and XRCC1/DNA ligase III in an alternative route for DNA double-strand breaks rejoining. J Biol Chem 279:55117–55126. doi:10.1074/jbc.M404524200

    CAS  PubMed  Google Scholar 

  32. Wang M, Wu W, Wu W, Rosidi B, Zhang L, Wang H, Iliakis G (2006) PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways. Nucleic Acids Res 34:6170–6182. doi:10.1093/nar/gkl840

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Sugimura K, Takebayashi S-I, Taguchi H, Takeda S, Okumura K (2008) PARP-1 ensures regulation of replication fork progression by homologous recombination on damaged DNA. J Cell Biol 183:1203–1212. doi:10.1083/jcb.200806068

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Gottipati P, Vischioni B, Schultz N, Solomons J, Bryant HE, Djureinovic T, Issaeva N, Sleeth K, Sharma RA, Helleday T (2010) Poly(ADP-ribose) polymerase is hyperactivated in homologous recombination-defective cells. Cancer Res 70:5389–5398. doi:10.1158/0008-5472.CAN-09-4716

    CAS  PubMed  Google Scholar 

  35. Wacker DA, Ruhl DD, Balagamwala EH, Hope KM, Zhang T, Kraus WL (2007) The DNA binding and catalytic domains of poly(ADP-ribose) polymerase 1 cooperate in the regulation of chromatin structure and transcription. Mol Cell Biol 27:7475–7485. doi:10.1128/MCB.01314-07

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Huletsky A, de Murcia G, Muller S, Hengartner M, Ménard L, Lamarre D, Poirier GG (1989) The effect of poly(ADP-ribosyl)ation on native and H1-depleted chromatin. A role of poly(ADP-ribosyl)ation on core nucleosome structure. J Biol Chem 264:8878–8886

    CAS  PubMed  Google Scholar 

  37. Pinnola A, Naumova N, Shah M, Tulin AV (2007) Nucleosomal core histones mediate dynamic regulation of poly(ADP-ribose) polymerase 1 protein binding to chromatin and induction of its enzymatic activity. J Biol Chem 282:32511–32519. doi:10.1074/jbc.M705989200

    CAS  PubMed  Google Scholar 

  38. Ding R, Smulson M (1994) Depletion of nuclear poly (ADP-ribose) polymerase by antisense RNA expression: influences on genomic stability, chromatin organization, and carcinogen cytotoxicity. Cancer Res 54(17):4627–4634

    CAS  PubMed  Google Scholar 

  39. Gottschalk AJ, Timinszky G, Kong SE, Jin J, Cai Y, Swanson SK, Washburn MP, Florens L, Ladurner AG, Conaway JW, Conaway RC (2009) Poly(ADP-ribosyl)ation directs recruitment and activation of an ATP-dependent chromatin remodeler. Proc Natl Acad Sci U S A 106:13770–13774. doi:10.1073/pnas.0906920106

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Ahel D, Horejsí Z, Wiechens N, Polo SE, Garcia-Wilson E, Ahel I, Flynn H, Skehel M, West SC, Jackson SP, Owen-Hughes T, Boulton SJ (2009) Poly(ADP-ribose)-dependent regulation of DNA repair by the chromatin remodeling enzyme ALC1. Science 325:1240–1243. doi:10.1126/science.1177321

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Erdélyi K, Bai P, Kovács I, Szabó E, Mocsár G, Kakuk A, Szabó C, Gergely P, Virág L (2009) Dual role of poly(ADP-ribose) glycohydrolase in the regulation of cell death in oxidatively stressed A549 cells. FASEB J 23:3553–3563. doi:10.1096/fj.09-133264

    PubMed Central  PubMed  Google Scholar 

  42. Frizzell KM, Gamble MJ, Berrocal JG, Zhang T, Krishnakumar R, Cen Y, Sauve AA, Kraus WL (2009) Global analysis of transcriptional regulation by poly(ADP-ribose) polymerase-1 and poly(ADP-ribose) glycohydrolase in MCF-7 human breast cancer cells. J Biol Chem 284:33926–33938. doi:10.1074/jbc.M109.023879

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Boudra MT, Bolin C, Chiker S, Fouquin A, Zaremba T, Vaslin L, Biard D, Cordelières FP, Mégnin-Chanet F, Favaudon V, Fernet M, Pennaneach V, Hall J (2014) PARP-2 depletion results in lower radiation cell survival but cell line-specific differences in poly(ADP-ribose) levels. Cell Mol Life Sci. Epub ahead of print

    Google Scholar 

  44. Uchiumi F, Watanabe T, Ohta R, Abe H, Tanuma S-I (2013) PARP1 gene expression is downregulated by knockdown of PARG gene. Oncol Rep 29:1683–1688. doi:10.3892/or.2013.2321

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Ambrose HE, Willimott S, Beswick RW, Dantzer F, de Murcia JM, Yelamos J, Wagner SD (2009) Poly(ADP-ribose) polymerase-1 ( PARP-1)-deficient mice demonstrate abnormal antibody responses. Immunology 127:178–186. doi:10.1111/j.1365-2567.2008.02921.x

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Ménissier de Murcia J, Ricoul M, Tartier L, Niedergang C, Huber A, Dantzer F, Schreiber V, Amé J-C, Dierich A, LeMeur M, Sabatier L, Chambon P, de Murcia G (2003) Functional interaction between PARP-1 and PARP-2 in chromosome stability and embryonic development in mouse. EMBO J 22:2255–2263. doi:10.1093/emboj/cdg206

    PubMed Central  PubMed  Google Scholar 

  47. Yélamos J, Monreal Y, Saenz L, Aguado E, Schreiber V, Mota R, Fuente T, Minguela A, Parrilla P, de Murcia G, Almarza E, Aparicio P, Ménissier-de Murcia J (2006) PARP-2 deficiency affects the survival of CD4 + CD8 + double-positive thymocytes. EMBO J 25:4350–4360. doi:10.1038/sj.emboj.7601301

    PubMed Central  PubMed  Google Scholar 

  48. Farrés J, Martín-Caballero J, Martínez C, Lozano JJ, Llacuna L, Ampurdanés C, Ruiz-Herguido C, Dantzer F, Schreiber V, Villunger A, Bigas A, Yélamos J (2013) PARP-2 is required to maintain hematopoiesis following sublethal γ-irradiation in mice. Blood 122:44–54. doi:10.1182/blood-2012-12-472845

    PubMed  Google Scholar 

  49. Yélamos J, Schreiber V, Dantzer F (2008) Toward specific functions of poly(ADP-ribose) polymerase-2. Trends Mol Med 14:169–178. doi:10.1016/j.molmed.2008.02.003

    PubMed  Google Scholar 

  50. Schreiber V, Ricoul M, Amé J, Dantzer F, Meder V, Spenlehauer C, Stiegler P, Niedergang C, Sabatier L, Favaudon V, Menissier-de Murcia J, de Murcia G (2006) PARP-2: structure-function relationship. In: Poly(ADP-Ribosy)ation edited by Alexander Bϋrkle ©2006 Landes biosecience and Springer Science+ Business media pp 13–31

    Google Scholar 

  51. Schreiber V, Amé J-C, Dollé P, Schultz I, Rinaldi B, Fraulob V, Ménissier-de Murcia J, de Murcia G (2002) Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1. J Biol Chem 277:23028–23036. doi:10.1074/jbc.M202390200

    CAS  PubMed  Google Scholar 

  52. Szántó M, Rutkai I, Hegedus C, Czikora Á, Rózsahegyi M, Kiss B, Virág L, Gergely P, Tóth A, Bai P (2011) Poly(ADP-ribose) polymerase-2 depletion reduces doxorubicin-induced damage through SIRT1 induction. Cardiovasc Res 92:430–438. doi:10.1093/cvr/cvr246

    PubMed  Google Scholar 

  53. Robert I, Dantzer F, Reina-San-Martin B (2009) PARP1 facilitates alternative NHEJ, whereas PARP2 suppresses IgH/c-myc translocations during immunoglobulin class switch recombination. J Exp Med 206:1047–1056. doi:10.1084/jem.20082468

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Kutuzov MM, Khodyreva SN, Amé J-C, Ilina ES, Sukhanova MV, Schreiber V, Lavrik OI (2013) Interaction of PARP-2 with DNA structures mimicking DNA repair intermediates and consequences on activity of base excision repair proteins. Biochimie 95:1208–1215. doi:10.1016/j.biochi.2013.01.007

    CAS  PubMed  Google Scholar 

  55. Szántó M, Brunyánszki A, Kiss B, Nagy L, Gergely P, Virág L, Bai P (2012) Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein. Cell Mol Life Sci 69:4079–4092. doi:10.1007/s00018-012-1003-8

    PubMed  Google Scholar 

  56. Dantzer F, Giraud-Panis M, Jaco I, Ame J-C, Schultz I, Blasco M, Koering C-E, Gilson E, Menissier-de Murcia J, de Murcia G, Schreiber V (2004) Functional Interaction between Poly(ADP-Ribose) Polymerase 2 (PARP-2) and TRF2: PARP Activity Negatively Regulates TRF2. Mol Cell Biol 24:1595–1607. doi:10.1128/MCB.24.4.1595-1607.2004

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Boehler C, Gauthier L, Yelamos J, Noll A, Schreiber V, Dantzer F (2011) Phenotypic characterization of PARP-1 and PARP-2 deficient mice and cells. Methods Mol Biol 780:313–336. doi:10.1007/978-1-61779-270-0_19

    CAS  PubMed  Google Scholar 

  58. Rulten SL, Fisher AEO, Robert I, Zuma MC, Rouleau M, Ju L, Poirier G, Reina-San-Martin B, Caldecott KW (2011) PARP-3 and APLF function together to accelerate nonhomologous end-joining. Mol Cell 41:33–45. doi:10.1016/j.molcel.2010.12.006

    CAS  PubMed  Google Scholar 

  59. Augustin A, Spenlehauer C, Dumond H, Ménissier-De Murcia J, Piel M, Schmit A-C, Apiou F, Vonesch J-L, Kock M, Bornens M, De Murcia G (2003) PARP-3 localizes preferentially to the daughter centriole and interferes with the G1/S cell cycle progression. J Cell Sci 116:1551–1562. doi:10.1242/jcs.00341

    CAS  PubMed  Google Scholar 

  60. Boehler C, Gauthier LR, Mortusewicz O, Biard DS, Saliou J-M, Bresson A, Sanglier-Cianferani S, Smith S, Schreiber V, Boussin F, Dantzer F (2011) Poly(ADP-ribose) polymerase 3 (PARP3), a newcomer in cellular response to DNA damage and mitotic progression. Proc Natl Acad Sci U S A 108:2783–2788. doi:10.1073/pnas.1016574108

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Bieche I, Pennaneach V, Driouch K, Vacher S, Zaremba T, Susini A, Lidereau R, Hall J (2013) Variations in the mRNA expression of poly(ADP-ribose) polymerases, poly(ADP-ribose) glycohydrolase and ADP-ribosylhydrolase 3 in breast tumors and impact on clinical outcome. Int J Cancer 133:2791–2800. doi:10.1002/ijc.28304

    CAS  PubMed  Google Scholar 

  62. Ben-Hur E, Utsumi H, Elkind M (1984) Inhibitors of poly (ADP-ribose) synthesis enhance X-ray killing of log-phase Chinese hamster cells. Radiat Res 555:546–555

    Google Scholar 

  63. Wahlberg E, Karlberg T, Kouznetsova E, Markova N, Macchiarulo A, Thorsell A-G, Pol E, Frostell Å, Ekblad T, Öncü D, Kull B, Robertson GM, Pellicciari R, Schüler H, Weigelt J (2012) Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors. Nat Biotechnol 30:283–288. doi:10.1038/nbt.2121

    CAS  PubMed  Google Scholar 

  64. Satoh MS, Lindahl T (1992) Role of poly(ADP-ribose) formation in DNA repair. Nature 356:356–358. doi:10.1038/356356a0

    CAS  PubMed  Google Scholar 

  65. Mortusewicz O, Amé J-C, Schreiber V, Leonhardt H (2007) Feedback-regulated poly(ADP-ribosyl)ation by PARP-1 is required for rapid response to DNA damage in living cells. Nucleic Acids Res 35:7665–7675. doi:10.1093/nar/gkm933

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Okano S, Lan L, Caldecott KW, Mori T, Yasui A (2003) Spatial and temporal cellular responses to single-strand breaks in human cells. Mol Cell Biol 23:3974–3981. doi:10.1128/MCB.23.11.3974-3981.2003

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Lan L, Nakajima S, Oohata Y, Takao M, Okano S, Masutani M, Wilson SH, Yasui A (2004) In situ analysis of repair processes for oxidative DNA damage in mammalian cells. Proc Natl Acad Sci U S A 101:13738–13743. doi:10.1073/pnas.0406048101

    PubMed Central  PubMed  Google Scholar 

  68. Noël G, Godon C, Fernet M, Giocanti N, Mégnin-Chanet F, Favaudon V (2006) Radiosensitization by the poly(ADP-ribose) polymerase inhibitor 4-amino-1,8-naphthalimide is specific of the S phase of the cell cycle and involves arrest of DNA synthesis. Mol Cancer Ther 5:564–574. doi:10.1158/1535-7163.MCT-05-0418

    PubMed  Google Scholar 

  69. Dungey FA, Löser DA, Chalmers AJ (2008) Replication-dependent radiosensitization of human glioma cells by inhibition of poly(ADP-Ribose) polymerase: mechanisms and therapeutic potential. Int J Radiat Oncol Biol Phys 72:1188–1197. doi:10.1016/j.ijrobp.2008.07.031

    CAS  PubMed  Google Scholar 

  70. Saleh-Gohari N, Bryant HE, Schultz N, Parker KM, Cassel TN, Helleday T (2005) Spontaneous homologous recombination is induced by collapsed replication forks that are caused by endogenous DNA single-strand breaks. Mol Cell Biol 25:7158–7169. doi:10.1128/MCB.25.16.7158-7169.2005

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913–917. doi:10.1038/nature03443

    CAS  PubMed  Google Scholar 

  72. Farmer H, McCabe N, Lord CJ, Tutt ANJ, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NMB, Jackson SP, Smith GCM, Ashworth A (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–921. doi:10.1038/nature03445

    CAS  PubMed  Google Scholar 

  73. Murai J, Huang SN, Renaud A, Zhang Y, Ji J, Takeda S, Morris J, Teicher B, Doroshow JH, Pommier Y (2014) Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther 13:433–443. doi:10.1158/1535-7163.MCT-13-0803

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Murai J, Huang SN, Das BB, Renaud A, Zhang Y, Doroshow JH, Ji J, Takeda S, Pommier Y (2012) Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res 72:5588–5599. doi:10.1158/0008-5472.CAN-12-2753

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Heacock ML, Stefanick DF, Horton JK, Wilson SH (2010) Alkylation DNA damage in combination with PARP inhibition results in formation of S-phase-dependent double-strand breaks. DNA Repair (Amst) 9:929–936. doi:10.1016/j.dnarep.2010.05.007

    CAS  Google Scholar 

  76. Horton JK, Stefanick DF, Naron JM, Kedar PS, Wilson SH (2005) Poly(ADP-ribose) polymerase activity prevents signaling pathways for cell cycle arrest after DNA methylating agent exposure. J Biol Chem 280:15773–15785. doi:10.1074/jbc.M413841200

    CAS  PubMed  Google Scholar 

  77. Kedar PS, Stefanick DF, Horton JK, Wilson SH (2012) Increased PARP-1 association with DNA in alkylation damaged, PARP-inhibited mouse fibroblasts. Mol Cancer Res 10:360–368. doi:10.1158/1541-7786.MCR-11-0477

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Helleday T (2011) The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings. Mol Oncol 5:387–393. doi:10.1016/j.molonc.2011.07.001

    CAS  PubMed  Google Scholar 

  79. Wang L, Mason KA, Ang KK, Buchholz T, Valdecanas D, Mathur A, Buser-Doepner C, Toniatti C, Milas L (2012) MK-4827, a PARP-1/-2 inhibitor, strongly enhances response of human lung and breast cancer xenografts to radiation. Invest New Drugs 30:2113–2120. doi:10.1007/s10637-011-9770-x

    Google Scholar 

  80. Ali M, Kamjoo M, Thomas HD, Kyle S, Pavlovska I, Babur M, Telfer BA, Curtin NJ, Williams KJ (2011) The clinically active PARP inhibitor AG014699 ameliorates cardiotoxicity but does not enhance the efficacy of doxorubicin, despite improving tumor perfusion and radiation response in mice. Mol Cancer Ther 10:2320–2329. doi:10.1158/1535-7163.MCT-11-0356

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Donawho CK, Luo Y, Penning TD, Bauch JL, Bouska JJ, Bontcheva-Diaz VD, Cox BF, DeWeese TL, Dillehay LE, Ferguson DC, Ghoreishi-Haack NS, Grimm DR, Guan R, Han EK, Holley-Shanks RR, Hristov B, Idler KB, Jarvis K, Johnson EF, Kleinberg LR, Klinghofer V, Lasko LM, Liu X, Marsh KC, McGonigal TP, Meulbroek JA, Olson AM, Palma JP, Rodriguez LE, Shi Y, Stavropoulos JA, Tsurutani AC, Zhu G, Rosenberg SH, Giranda VL, Frost DJ (2007) ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res 13:2728–2737. doi:10.1158/1078-0432.CCR-06-3039

    CAS  PubMed  Google Scholar 

  82. Calabrese CR, Almassy R, Barton S, Batey MA, Calvert AH, Canan-Koch S, Durkacz BW, Hostomsky Z, Kumpf RA, Kyle S, Li J, Maegley K, Newell DR, Notarianni E, Stratford IJ, Skalitzky D, Thomas HD, Wang L-Z, Webber SE, Williams KJ, Curtin NJ (2004) Anticancer Chemosensitization and Radiosensitization by the Novel Poly(ADP-ribose) Polymerase-1 Inhibitor AG14361. JNCI J Natl Cancer Inst 96:56–67. doi:10.1093/jnci/djh005

    CAS  Google Scholar 

  83. Shelton JW, Waxweiler TV, Landry J, Gao H, Xu Y, Wang L, El-Rayes B, Shu H-KG (2013) In vitro and in vivo enhancement of chemoradiation using the oral PARP inhibitor ABT-888 in colorectal cancer cells. Int J Radiat Oncol Biol Phys 86:469–476. doi:10.1016/j.ijrobp.2013.02.015

    CAS  PubMed  Google Scholar 

  84. Albert JM, Cao C, Kim KW, Willey CD, Geng L, Xiao D, Wang H, Sandler A, Johnson DH, Colevas AD, Low J, Rothenberg ML, Lu B (2007) Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models. Clin Cancer Res 13:3033–3042. doi:10.1158/1078-0432.CCR-06-2872

    Google Scholar 

  85. Senra JM, Telfer BA, Cherry KE, McCrudden CM, Hirst DG, O’Connor MJ, Wedge SR, Stratford IJ (2011) Inhibition of PARP-1 by olaparib (AZD2281) increases the radiosensitivity of a lung tumor xenograft. Mol Cancer Ther 10:1949–1958. doi:10.1158/1535-7163.MCT-11-0278

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Chow JPH, Man WY, Mao M, Chen H, Cheung F, Nicholls J, Tsao SW, Li Lung M, Poon RYC (2013) PARP1 is overexpressed in nasopharyngeal carcinoma and its inhibition enhances radiotherapy. Mol Cancer Ther 12:251725–251728. doi:10.1158/1535-7163.MCT-13-0010

    Google Scholar 

  87. Khan K, Araki K, Wang D, Li G, Li X, Zhang J, Xu W, Hoover RK, Lauter S, O’Malley B, Lapidus RG, Li D (2010) Head and neck cancer radiosensitization by the novel poly(ADP-ribose) polymerase inhibitor GPI-15427. Head Neck 32:381–391. doi:10.1002/hed.21195

    PubMed  Google Scholar 

  88. Clarke MJ, Mulligan EA, Grogan PT, Mladek AC, Carlson BL, Schroeder MA, Curtin NJ, Lou Z, Decker PA, Wu W, Plummer ER, Sarkaria JN (2009) Effective sensitization of temozolomide by ABT-888 is lost with development of temozolomide resistance in glioblastoma xenograft lines. Mol Cancer Ther 8:407–414. doi:10.1158/1535-7163.MCT-08-0854

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Russo AL, Kwon H-C, Burgan WE, Carter D, Beam K, Weizheng X, Zhang J, Slusher BS, Chakravarti A, Tofilon PJ, Camphausen K (2009) In vitro and in vivo radiosensitization of glioblastoma cells by the poly (ADP-ribose) polymerase inhibitor E7016. Clin Cancer Res 15:607–612. doi:10.1158/1078-0432.CCR-08-2079

    CAS  PubMed  Google Scholar 

  90. Venere M, Hamerlik P, Wu Q, Rasmussen RD, Song LA, Vasanji A, Tenley N, Flavahan WA, Hjelmeland AB, Bartek J, Rich JN (2014) Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells. Cell Death Differ 21:258–269. doi:10.1038/cdd.2013.136

    Google Scholar 

  91. Mueller S, Bhargava S, Molinaro AM, Yang X, Kolkowitz I, Olow A, Wehmeijer N, Orbach S, Chen J, Matthay KK, Haas-Kogan DA (2013) Poly (ADP-Ribose) polymerase inhibitor MK-4827 together with radiation as a novel therapy for metastatic neuroblastoma. Anticancer Res 33:755–762

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Horsman MR (1995) Nicotinamide and other benzamide analogs as agents for overcoming hypoxic cell radiation resistance in tumours. A review. Acta Oncol 34:571–587

    CAS  PubMed  Google Scholar 

  93. Liu SK, Coackley C, Krause M, Jalali F, Chan N, Bristow RG (2008) A novel poly(ADP-ribose) polymerase inhibitor, ABT-888, radiosensitizes malignant human cell lines under hypoxia. Radiother Oncol 88:258–268. doi:10.1016/j.radonc.2008.04.005

    CAS  PubMed  Google Scholar 

  94. Baker DG, Krochak RJ (1989) The response of the microvascular system to radiation: a review. Cancer Invest 7:287–294

    CAS  PubMed  Google Scholar 

  95. Dubner D, Gisone P, Jaitovich I, Perez M (1995) Free radicals production and estimation of oxidative stress related to gamma irradiation. Biol Trace Elem Res 47:265–270. doi:10.1007/BF02790126

    CAS  PubMed  Google Scholar 

  96. Jagtap P, Szabó C (2005) Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nat Rev Drug Discov 4:421–440. doi:10.1038/nrd1718

    CAS  PubMed  Google Scholar 

  97. Clempus RE, Griendling KK (2006) Reactive oxygen species signaling in vascular smooth muscle cells. Cardiovasc Res 71:216–225. doi:10.1016/j.cardiores.2006.02.033

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Affar EB, Germain M, Poirier GG (2000) Role of poly(ADP-ribose) polymerase in cell death. In: de Murcia G, Shall S (eds) From DNA damage stress signal. To cell death. Oxford University Press, New York, pp 125–150

    Google Scholar 

  99. Szabo C (2000) Activation of poly(ADP-ribose) polymerase in the pathogenesis of ischaemia-reperfusion injury. In: de Murcia G, Shall S (eds) From DNA damage stress signal. To cell death. Poly ADP-ribosylation react. Oxford University Press, New York, pp 151–176

    Google Scholar 

  100. Rajesh M, Mukhopadhyay P, Bátkai S, Godlewski G, Haskó G, Liaudet L, Pacher P (2006) Pharmacological inhibition of poly(ADP-ribose) polymerase inhibits angiogenesis. Biochem Biophys Res Commun 350:352–357. doi:10.1016/j.bbrc.2006.09.049

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Rajesh M, Mukhopadhyay P, Godlewski G, Bátkai S, Haskó G, Liaudet L, Pacher P (2006) Poly(ADP-ribose)polymerase inhibition decreases angiogenesis. Biochem Biophys Res Commun 350:1056–1062. doi:10.1016/j.bbrc.2006.09.160

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Beller CJ, Radovits T, Seres L, Kosse J, Krempien R, Gross M-L, Penzel R, Berger I, Huber PE, Hagl S, Szabó C, Szabó G (2006) Poly(ADP-ribose) polymerase inhibition reverses vascular dysfunction after gamma-irradiation. Int J Radiat Oncol Biol Phys 65:1528–1535. doi:10.1016/j.ijrobp.2006.03.058

    CAS  PubMed  Google Scholar 

  103. Beller CJ, Kosse J, Radovits T, Gerö D, Krempien R, Gross M-L, Berger I, Hagl S, Szabó C, Szabó G (2006) Poly(ADP-ribose) polymerase inhibition combined with irradiation: a dual treatment concept to prevent neointimal hyperplasia after endarterectomy. Int J Radiat Oncol Biol Phys 66:867–875. doi:10.1016/j.ijrobp.2006.06.055

    CAS  PubMed  Google Scholar 

  104. Radovits T, Lin L, Zotkina J, Gero D, Szabó C, Karck M, Szabó G (2007) Poly(ADP-ribose) polymerase inhibition improves endothelial dysfunction induced by reactive oxidant hydrogen peroxide in vitro. Eur J Pharmacol 564:158–166. doi:10.1016/j.ejphar.2007.02.060

    CAS  PubMed  Google Scholar 

  105. Yarnold J, Brotons M-CV (2010) Pathogenetic mechanisms in radiation fibrosis. Radiother Oncol 97:149–161. doi:10.1016/j.radonc.2010.09.002

    CAS  PubMed  Google Scholar 

  106. Milliat F, François A, Isoir M, Deutsch E, Tamarat R, Tarlet G, Atfi A, Validire P, Bourhis J, Sabourin J-C, Benderitter M (2006) Influence of endothelial cells on vascular smooth muscle cells phenotype after irradiation: implication in radiation-induced vascular damages. Am J Pathol 169:1484–1495. doi:10.2353/ajpath.2006.060116

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Finnson KW, Parker WL, ten Dijke P, Thorikay M, Philip A (2008) ALK1 opposes ALK5/Smad3 signaling and expression of extracellular matrix components in human chondrocytes. J Bone Miner Res 23:896–906. doi:10.1359/jbmr.080209

    CAS  PubMed  Google Scholar 

  108. Cordenonsi M, Dupont S, Maretto S, Insinga A, Imbriano C, Piccolo S (2003) Links between tumor suppressors: p53 is required for TGF-beta gene responses by cooperating with Smads. Cell 113:301–314

    CAS  PubMed  Google Scholar 

  109. Hageman J, Eggen BJ, Rozema T, Damman K, Kampinga HH, Coppes RP (2005) Radiation and transforming growth factor-beta cooperate in transcriptional activation of the profibrotic plasminogen activator inhibitor-1 gene. Clin Cancer Res 11:5956–5964. doi:10.1158/1078-0432.CCR-05-0427

    CAS  PubMed  Google Scholar 

  110. Niemantsverdriet M, de Jong E, Langendijk JA, Kampinga HH, Coppes RP (2010) Synergistic induction of profibrotic PAI-1 by TGF-β and radiation depends on p53. Radiother Oncol 97:33–35. doi:10.1016/j.radonc.2010.04.002

    Google Scholar 

  111. Scharpfenecker M, Kruse JJCM, Sprong D, Russell NS, Ten Dijke P, Stewart FA (2009) Ionizing radiation shifts the PAI-1/ID-1 balance and activates notch signaling in endothelial cells. Int J Radiat Oncol Biol Phys 73:506–513. doi:10.1016/j.ijrobp.2008.09.052

    CAS  PubMed  Google Scholar 

  112. Wang Y, Wang L, Zhang F, Zhang C, Deng S, Wang R, Zhang Y, Huang D, Huang K (2013) Inhibition of PARP prevents angiotensin II-induced aortic fibrosis in rats. Int J Cardiol 167:2285–2293. doi:10.1016/j.ijcard.2012.06.050

    PubMed  Google Scholar 

  113. Lei P, Jiang Z, Zhu H, Li X, Su N, Yu X (2012) Poly(ADP-ribose) polymerase-1 in high glucose-induced epithelial-mesenchymal transition during peritoneal fibrosis. Int J Mol Med 29:472–478. doi:10.3892/ijmm.2011.859

    PubMed  Google Scholar 

  114. Palfi A, Toth A, Hanto K, Deres P, Szabados E, Szereday Z, Kulcsar G, Kalai T, Hideg K, Gallyas F, Sumegi B, Toth K, Halmosi R (2006) PARP inhibition prevents postinfarction myocardial remodeling and heart failure via the protein kinase C/glycogen synthase kinase-3beta pathway. J Mol Cell Cardiol 41:149–159. doi:10.1016/j.yjmcc.2006.03.427

    CAS  PubMed  Google Scholar 

  115. Pacher P, Liaudet L, Mabley JG, Cziráki A, Haskó G, Szabó C (2006) Beneficial effects of a novel ultrapotent poly(ADP-ribose) polymerase inhibitor in murine models of heart failure. Int J Mol Med 17:369–375

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Chiu J, Farhangkhoee H, Xu BY, Chen S, George B, Chakrabarti S (2008) PARP mediates structural alterations in diabetic cardiomyopathy. J Mol Cell Cardiol 45:385–393. doi:10.1016/j.yjmcc.2008.06.009

    CAS  PubMed  Google Scholar 

  117. Bartha E, Kiss GN, Kalman E, Kulcsár G, Kálai T, Hideg K, Habon T, Sumegi B, Toth K, Halmosi R (2008) Effect of L-2286, a poly(ADP-ribose)polymerase inhibitor and enalapril on myocardial remodeling and heart failure. J Cardiovasc Pharmacol 52:253–261. doi:10.1097/FJC.0b013e3181855cef

    CAS  PubMed  Google Scholar 

  118. Bartha E, Solti I, Kereskai L, Lantos J, Plozer E, Magyar K, Szabados E, Kálai T, Hideg K, Halmosi R, Sumegi B, Toth K (2009) PARP inhibition delays transition of hypertensive cardiopathy to heart failure in spontaneously hypertensive rats. Cardiovasc Res 83:501–510. doi:10.1093/cvr/cvp144

    CAS  PubMed  Google Scholar 

  119. Pagano A, Métrailler-Ruchonnet I, Aurrand-Lions M, Lucattelli M, Donati Y, Argiroffo CB (2007) Poly(ADP-ribose) polymerase-1 (PARP-1) controls lung cell proliferation and repair after hyperoxia-induced lung damage. Am J Physiol Lung Cell Mol Physiol 293:L619–L629. doi:10.1152/ajplung.00037.2007

    Google Scholar 

  120. Anjos SM, Robert R, Waller D, Zhang DL, Balghi H, Sampson HM, Ciciriello F, Lesimple P, Carlile GW, Goepp J, Liao J, Ferraro P, Phillipe R, Dantzer F, Hanrahan JW, Thomas DY (2012) Decreasing poly(ADP-Ribose) polymerase activity restores ΔF508 CFTR trafficking. Front Pharmacol 3:165. doi:10.3389/fphar.2012.00165

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Favaudon V, Caplier L, Monceau V, Pouzoulet F, Sayarath M, Fouillade C, Poupon MF, Brito I, Hupé P, Bourhis J, Hall J, Fontaine JJ, Vozenin MC (2014) Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice. Sci Transl Med 6:245ra93. doi:10.1126/scitranslmed.3008973

    Google Scholar 

  122. Zackrisson BU, Nyström UH, Ostbergh P (1991) Biological response in vitro to pulsed high dose rate electrons from a clinical accelerator. Acta Oncol 30:747–751

    CAS  PubMed  Google Scholar 

  123. Ponette V, Le Péchoux C, Deniaud-Alexandre E, Fernet M, Giocanti N, Tourbez H, Favaudon V (2000) Hyperfast, early cell response to ionizing radiation. Int J Radiat Biol 76:1233–1243

    CAS  PubMed  Google Scholar 

  124. Fernet M, Ponette V, Deniaud-Alexandre E, Ménissier-De Murcia J, De Murcia G, Giocanti N, Megnin-Chanet F, Favaudon V (2000) Poly(ADP-ribose) polymerase, a major determinant of early cell response to ionizing radiation. Int J Radiat Biol 76:1621–1629

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Research in Inserm U612 is supported by Inserm and Institut Curie and is part of the Comprehensive Cancer Centre “SIRIC” program (INCa 2011-189). CF is supported by INCa (PL-BIO 2013-11) and AF by a PhD fellowship from the French Ministry of Research. MTB was supported by Institute Curie’s International Postdoctoral fellow program.

Author information

Authors and Affiliations

  1. Inserm U612, Institut Curie, Bats 110–112, Centre Universitaire, 91405, Orsay, France

    Charles Fouillade, Alexis Fouquin, Mohammed-Tayyib Boudra, Vincent Favaudon, Vincent Pennaneach & Janet Hall

Authors
  1. Charles Fouillade
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexis Fouquin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohammed-Tayyib Boudra
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vincent Favaudon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vincent Pennaneach
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Janet Hall
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Janet Hall .

Editor information

Editors and Affiliations

  1. Northern Institute for Cancer Research and Newcastle University Institute for Ageing Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom

    Nicola J. Curtin

  2. CRUK-MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom

    Ricky A. Sharma

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Fouillade, C., Fouquin, A., Boudra, MT., Favaudon, V., Pennaneach, V., Hall, J. (2015). Radiosensitisation by Poly(ADP-ribose) Polymerase Inhibition. In: Curtin, N., Sharma, R. (eds) PARP Inhibitors for Cancer Therapy. Cancer Drug Discovery and Development, vol 83. Humana Press, Cham. https://doi.org/10.1007/978-3-319-14151-0_11

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-14151-0_11

  • Published:

  • Publisher Name: Humana Press, Cham

  • Print ISBN: 978-3-319-14150-3

  • Online ISBN: 978-3-319-14151-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation