Abstract
Resistance to anticancer radiation treatment has a strong negative impact upon morbidity and mortality related to prostate cancer (Liu et al., Radiother Oncol 88(2):258–268, 2008).
This justifies the great interest in the advancing efforts toward the design of new molecularly-targeted agents which could improve the therapeutic ratio for aggressive prostate cancers via tumor radio-sensitization (Fan et al., Cancer Res 64(23):8526–8533, 2004).
Tumor progression of prostate cancer is associated, as in most of human malignancies, with the sequential loss of function of genes that normally protect against DNA damage.
Malignant prostate cells respond to both endogenous and exogenous DNA damage through complex signaling responses. Due to a specific genetic background, or in an acquired manner during tumor progression, PC cell clones show defect in either DNA single-strand break (SSB) and/or double-strand break (DSB) repair, and/or base damage repair (Stewart et al., Biochem Pharmacol 81(2):203–210, 2011), DSBs are the principal responsible for cell killing due to ionizing radiation (Ward 1988).
A defective DNA double-strand break repair increases genetic instability of PC cells, could be considered as part of their “mutator” phenotype (Tyson et al., Prostate 67:1601–1613, 2007).
During the last decades, it has emerged the concept of “synthetic lethality” (Chalmers et al., Semin Radiat Oncol 20(4):274–281, 2010).
This concept derives from the observation that the use of a single inhibitor of a DNA repair enzyme leads to the selective killing of tumor cells, bearing a second DNA repair defect (Bryant et al., Nature 434(7035):913–917, 2005; Jones and Plummer, Br J Radiol 81(Spec No 1):S2–S5, 2008; Fong et al., N Engl J Med 361:123–134, 2009).
To this end, PARP inhibitors are the well-known class of drugs that have recently been proposed to reach synthetic lethality in DNA repair-defective, radio-resistant prostate tumors.
This chapter aims to provide a framework for understanding the recent therapeutic trends designed to overcome radioresistance in prostate cancer via synthetic lethality, we review what it is actually known about the structures and functions of the members of the PARP family of enzymes, outlining a series of open questions that should be addressed in the short time to better guide the development (and the safe clinical use) of PARP inhibitors as new anticancer agents for prostate cancer (Cybulski et al., Cancer Res 64:1215–1219, 2004; Stewart et al., Biochem Pharmacol 81(2):203–210, 2011).
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Albert JM, Cao C, Kim KW et al (2007) Inhibition of poly(ADPRibose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models. Clin Cancer Res 13:3033–3042
Ali M, Telfer BA, McCrudden C et al (2009) Vasoactivity of AG014699, a clinically active small molecule inhibitor of poly(ADP-ribose) polymerase: a contributory factor to chemopotentiation in vivo? Clin Cancer Res 15:6106–6112
Andrabi SA et al (2006) Poly(ADP-ribose) (PAR) polymer is a death signal. Proc Natl Acad Sci USA 103:18308–18313
Antonarakis ES, Armstrong AJ (2011) Emerging therapeutic approaches in the management of metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis 14(3):206–218, Review
Ashworth A (2008) Drug resistance caused by reversion mutation. Cancer Res 68:10021–10023
Barreto-Andrade JC, Efimova EV, Mauceri HJ, Beckett MA, Sutton HG, Darga TE, Vokes EE, Posner MC, Kron SJ, Weichselbaum RR (2011) Response of human prostate cancer cells and tumors to combining PARP inhibition with ionizing radiation. Mol Cancer Ther 10(7):1185–1193
Berger SJ, Sudar DC, Berger NA (1986) Metabolic consequences of DNA damage: DNA damage induces alterations in glucose metabolism by activation of poly (ADP-ribose) polymerase. Biochem Biophys Res Commun 134:227–232
Bernstein C, Bernstein H, Payne CM, Garewal H (2002) DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis. Mutat Res 511(2):145–178
Bertrand P, Saintigny Y et al (2004) p53’s double life: transactivation-independent repression of homologous recombination. Trends Genet 20:235–243
Bill-Axelson A, Holmberg L, Ruutu M, Haggman M, Andersson SO, Bratell S et al (2005) Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 352:1977–1984
Bindra RS, Glazer PM (2005) Genetic instability and the tumor microenvironment: towards the concept of microenvironment-induced mutagenesis. Mutat Res 569:75–85
Boehler C et al (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
Bristow RG, Hill P (1998) Molecular and cellular basis of radiotherapy. In: Tannock IF, Hill RP (eds) The basic science of oncology. McGraw-Hill, Toronto, pp 295–321
Bristow RG, Ozcelik H, Jalali F, Chan N, Vesprini D (2007) Homologous recombination and prostate cancer: a model for novel DNA repair targets and therapies. Radiother Oncol 83:220–230
Bromfield GP, Meng A, Warde P, Bristow RG (2003) Cell death in irradiated prostate epithelial cells: role of apoptotic and clonogenic cell kill. Prostate Cancer Prostatic Dis 6:73–85
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(7035):913–917
Calabrese CR et al (2003) Identification of potent non-toxic poly(ADPribose) polymerase-1 (PARP-1) inhibitors: chemopotentiation and pharmacological studies. Clin Cancer Res 9:2711–2718
Calabrese CR, Almassy R, Barton S et al (2004a) Anticancer chemosensitization and radiosensitization by the novel poly(ADPribose) polymerase-1 inhibitor AG14361. J Natl Cancer Inst 96:56–67
Calabrese CR et al (2004b) Preclinical evaluation of a novel poly(ADPribose) polymerase-1 (PARP-1) inhibitor, AG14361, with significant anticancer chemo- and radio-sensitization activity. J Natl Cancer Inst 96:56–67
Carnell DM, Smith RE, Daley FM, Saunders MI, Bentzen SM, Hoskin PJ (2006) An immunohistochemical assessment of hypoxia in prostate carcinoma using pimonidazole: implications for radioresistance. Int J Radiat Oncol Biol Phys 65:91–99
Carson DA, Carrera CJ, Wasson DB, Yamanaka H (1988) Programmed cell death and adenine deoxynucleotide metabolism in human lymphocytes. Adv Enzyme Regul 27:395–404
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(4):274–281
Chan N, Milosevic M, Bristow RG (2007) Tumor hypoxia, DNA repair and prostate cancer progression: new targets and new therapies. Future Oncol 3:329–341
Choudhury A, Cuddihy A, Bristow RG (2006) Radiation and new molecular agents part I: targeting ATM-ATR checkpoints, DNA repair, and the proteasome. Semin Radiat Oncol 16:51–58
Cohen-Armon M et al (2004) Long-term memory requires polyADP-ribosylation. Science 304:1820–1822
Collis SJ, Sangar VK, Tighe A et al (2002) Development of a novel rapid assay to assess the fidelity of DNA double-strand-break repair in human tumour cells. Nucleic Acids Res 30:E1
Collis SJ, DeWeese TL et al (2005) The life and death of DNA-PK. Oncogene 24:949–961
Curtin NJ (2005) PARP inhibitors for cancer therapy. Expert Rev Mol Med 7:1–20. Together with reference 15, excellent reviews describing the therapeutic promise of PARP Identification of a PAR-binding motif that mediates selective interaction between PAR and protein partners. inhibitors in cancer treatment or in inflammatory diseases
Curtin NJ (2012) Poly(ADP-ribose) polymerase (PARP) and PARP inhibitors. Drug Discov Today Dis Mod Target DNA Repair 9(2):e51–e58
Cybulski C, Gorski B, Debniak T et al (2004) NBS1 is a prostate cancer susceptibility gene. Cancer Res 64:1215–1219
D’Amours D, Desnoyers S, D’Silva I et al (1999) Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem J 342:249–268
Dantzer F, de la Rubia G, Menissier-De Murcia J et al (2000) Base excision repair is impaired in mammalian cells lacking poly(ADP-ribose) polymerase-1. Biochemistry 39:7559–7569
David KK, Andrabi SA, Dawson TM, Dawson VL (2009) Parthanatos, a messenger of death. Front Biosci 14:1116–1128
de Murcia G, Ménissier de Murcia J (1994) Poly(ADP-ribose) polymerase: a molecular nick-sensor. Trends Biochem Sci 19:172–176
Delaney CA et al (2000) Potentiation of temozolomide and topotecan growth inhibition and cytotoxicity by novel poly (adenosine diphosphoribose) polymerase inhibitors in a panel of human tumor cell lines. Clin Cancer Res 6:2860–2867
Donawho CK, Luo Y, Luo Y, Penning TD, Bauch JL, Bouska JJ et al (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
Dong JT (2006) Prevalent mutations in prostate cancer. J Cell Biochem 97:433–447
Dungey FA, Loser 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
Edwards SL et al (2008) Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451:1111–1115
Efimova EV, Mauceri HJ, Golden DW, Labay E, Bindokas VP, Darga TE et al (2010) Poly(ADP-ribose) polymerase inhibitor induces accelerated senescence in irradiated breast cancer cells and tumors. Cancer Res 70:6277–6282
Elliott B, Jasin M (2002) Double-strand breaks and translocations in cancer. Cell Mol Life Sci 59:373–385
Erkko H, Xia B, Nikkila J et al (2007) A recurrent mutation in PALB2 in Finnish cancer families. Nature 446:316–319
Escargueil AE, Soares DG, Salvador M, Larsen AK, Henriques JA (2008) What histone code for DNA repair? Mutat Res 658(3):259–270
Esgueva R, Park K, Kim R, Kitabayashi N, Barbieri CE, Dorsey PJ Jr, Abraham C, Banerjee S, Leung RA, Tewari AK, Terry S, Shevchuk MM, Rickman DS, Rubin MA, Weill Cornell Medical College (2012) Next-generation prostate cancer biobanking: toward a processing protocol amenable for the International Cancer Genome Consortium. Diagn Mol Pathol 21(2):61–68
Fan R, Kumaravel TS, Jalali F, Marrano P, Squire JA, Bristow RG (2004) Defective DNA strand break repair after DNA damage in prostate cancer cells: implications for genetic instability and prostate cancer progression. Cancer Res 64(23):8526–8533
Fang Y et al (2006) BubR1 is involved in regulation of DNA damage responses. Oncogene 25:3598–3605. doi:10.1038/sj.onc.1209392
Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–921
Farzaneh F, Zalin R, Brill D, Shall S (1982) DNA strand breaks and ADP-ribosyl transferase activation during cell differentiation. Nature 300:362–366
Fong PC, Boss DS, Yap TA et al (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361:123–134
Giner H et al (1992) Overproduction and large-scale purification of the human poly(ADP-ribose) polymerase using a baculovirus expression system. Gene 114:279–283
Goldberg S, Visochek L, Giladi E, Gozes I, Cohen-Armon M (2009) PolyADP-ribosylation is required for long-term memory formation in mammals. J Neurochem 111:72–79
Grube K et al (1991) Direct stimulation of poly(ADP-ribose) polymerase in permeabilised cells by double-stranded DNA oligomers. Anal Biochem 193:236–239
Guirouilh-Barbat J, Huck S et al (2004) Impact of the KU80 pathway on NHEJ-induced genome rearrangements in mammalian cells. Mol Cell 14:611–623
Hakame A et al (2008) The expanding field of poly(ADP-ribosyl)ation reactions. EMBO Rep 9:1094–1100
Hansen K, Kelly M (2000) Review of mammalian DNA repair and translational implications. J Pharmacol Exp Ther 295(1):1–9
Hoeijmakers JH (2001) Genome maintenance mechanisms for preventing cancer. Nature 411:360–374
Horsburgh S, Matthew A, Bristow RG, Trachtenberg J (2005) Male BRCA1 and BRCA2 mutation carriers: a pilot study investigating medical characteristics of patients participating in a prostate cancer prevention clinic. Prostate 65:124–129
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
Horton JK, Wilson SH (2007) Hypersensitivity phenotypes associated with genetic and synthetic inhibitor-induced base excision repair deficiency. DNA Repair (Amst) 6:530–543
Huang Q, Shen HM (2009) To die or to live: the dual role of poly(ADP-ribose) polymerase-1 in autophagy and necrosis under oxidative stress and DNA damage. Autophagy 5:273–276
Huang Q, Wu YT, Tan HL, Ong CN, Shen HM (2009) A novel function of poly(ADP-ribose) polymerase-1 in modulation of autophagy and necrosis under oxidative stress. Cell Death Differ 16:264–277
Johnstone AP, Williams GT (1982) Role of DNA breaks and ADP-ribosyl transferase activity in eukaryotic differentiation demonstrated in human lymphocytes. Nature 300:368–370
Jones C, Plummer ER (2008) PARP inhibitors and cancer therapy - early results and potential applications. Br J Radiol 81(Spec No 1):S2–S5
Ju BG et al (2004) Activating the PARP-1 sensor component of the groucho–TLE1 corepressor complex mediates a CaMKinase IIδ-dependent neurogenic gene activation pathway. Cell 119:815–829
Juarez-Salinas H, Sims JL, Jacobson MK (1979) Poly(ADP-ribose) levels in carcinogen-treated cells. Nature 282:740–741
Kastan MB, Bartek J (2004) Cell-cycle checkpoints and cancer. Nature 432:316–323
Kickhoefer VA, Siva AC, Kedersha NL, Inman EM, Ruland C, Streuli M, Rome LH (1999) The 193-kD vault protein, VPARP, is a novel poly(ADP-ribose) polymerase. J Cell Biol 146(5):917–928
Konishi Y et al (1986) Possible model of liver carcinogenesis using inhibitors of NAD + ADP ribosyl transferase in rats. Toxicol Pathol 14:483–488
Levy-Lahad E, Friedman E (2007) Cancer risks among BRCA1 and BRCA2 mutation carriers. Br J Cancer 96:11–15
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(2):258–268
Ljungman M (2009) Targeting the DNA damage response in cancer. Chem Rev 109:2929–2950
Lleonart ME, Artero-Castro A, Kondoh H (2009) Senescence induction; a possible cancer therapy. Mol Cancer 8:3
Loeb LA, Loeb KR, Anderson JP (2003) Multiple mutations and cancer. Proc Natl Acad Sci USA 100:776–781
Martin-Oliva D, Aguilar-Quesada R, O’Valle F et al (2006) Inhibition of poly(ADP-ribose) polymerase modulates tumor-related gene expression, including hypoxia-inducible factor-1 activation, during skin carcinogenesis. Cancer Res 66:5744–5756
Mendes-Pereira AM, Martin SA, Brough R, McCarthy A, Taylor JR, Kim JS et al (2009) Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol Med 1:315–322
Meng AX, Jalalia F, Cuddihya A, Chan N, Bindrab RS, Glazerb PM, Robert G (2005) Bristow Hypoxia down-regulates DNA double strand break repair gene expression in prostate cancer cells. Radiother Oncol 76:168–176
Menissier de Murcia J et al (1997) Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc Natl Acad Sci USA 94:7303–7307
Midorikawa R, Takei Y, Hirokawa N (2006) KIF4 motor regulates activity-dependent neuronal survival by suppressing PARP-1 enzymatic activity. Cell 125:371–383
Miknyoczki SJ et al (2003) Chemopotentiation of temozolomide, irinotecan, and cisplatin activity by CEP-6800, a poly(ADP-ribose) polymerase inhibitor. Mol Cancer Ther 2:371–382
Morrison C et al (1997) Genetic interaction between PARP and DNA-PK in V(D)J. Recombination and tumorigenesis. Nat Genet 17:479–482
Munoz-Gamez JA et al (2009) PARP-1 is involved in autophagy induced by DNA damage. Autophagy 5:61–74
Nichol AM, Warde P, Bristow RG (2005) Optimal treatment of intermediate-risk prostate carcinoma with radiotherapy: clinical and translational issues. Cancer 104:891–905
Noel G, Godon C, Fernet M et al (2006) Radiosensitization by the poly(ADPribose) 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
Ogata N, Ueda K, Kagamiyama H, Hayaishi O (1980) ADP-ribosylation of histone H1. Identification of glutamic acid residues 2, 14, and the COOH-terminal lysine residue as modification sites. J Biol Chem 255:7616–7620
Oliver AW et al (2004) Crystal structure of the catalytic fragment of murine poly(ADP-ribose) polymerase-2. Nucleic Acids Res 32:456–464
Overgaard J (2007) Hypoxic radiosensitization: adored and ignored. J Clin Oncol 25:4066–4074
Pacher P, Szabo C (2007) Role of poly(ADP-ribose) polymerase 1 (PARP-1) in cardiovascular diseases: the therapeutic potential of PARP inhibitors. Cardiovasc Drug Rev 25:235–260
Palma JP et al (2009) ABT-888 confers broad in vivo activity in combination with temozolomide in diverse tumours. Clin Cancer Res 15:7277–7290
Pfieffer R et al (1999) Quantitative nonisotopic immuno-dot-blot method for the assessment cellular poly(ADP-ribosyl)ation capacity. Anal Biochem 275:118–122
Pihan GA, Purohit A, Wallace J, Malhotra R, Liotta L, Doxsey SJ (2001) Centrosome defects can account for cellular and genetic changes that characterize prostate cancer progression. Cancer Res 61:2212–2219
Pleschke JM, Kleczkowska HE, Strohm M, Althaus FR (2000) Poly(ADP-ribose) binds to specific domains in DNA damage checkpoint proteins. J Biol Chem 275:40974–40980
Plummer R, Jones C, Middleton M, Wilson R, Evans J, Olsen A et al (2008) Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. Clin Cancer Res 14:7917–7923
Pollack A, Hanlon A et al (2003) Radiation therapy dose escalation for prostate cancer: a rationale for IMRT. World J Urol 21:200–208
Powell C, Mikropoulos C, Kaye SB, Nutting CM, Bhide SA, Newbold K et al (2010) Pre-clinical and clinical evaluation of PARP inhibitors as tumor-specific radiosensitizers. Cancer Treat Rev 36:566–575
Rajesh M, Mukhopadhyay P, Batkai S et al (2006a) Pharmacological inhibition of poly(ADP-ribose) polymerase inhibits angiogenesis. Biochem Biophys Res Commun 350:352–357
Rajesh M, Mukhopadhyay P, Godlewski G et al (2006b) Poly(ADPribose) polymerase inhibition decreases angiogenesis. Biochem Biophys Res Commun 350:1056–1062
Riballo E, Kuhne M et al (2004) A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci. Mol Cell 16:715–724
Richardson C, Stark JM et al (2004) Rad51 overexpression promotes alternative double-strand break repair pathways and genome instability. Oncogene 23:546–553
Rodon J, Iniesta MD, Papadopoulos K (2009) Development of PARP inhibitors in oncology. Expert Opin Investig Drugs 18:31–43
Roninson IB (2003) Tumor cell senescence in cancer treatment. Cancer Res 63:2705–2715
Rothkamm K, Kruger I et al (2003) Pathways of DNA double-strand break repair during the mammalian cell cycle. Mol Cell Biol 23:5706–5715
Rouleau M, Patel A, Hendzel MJ, Kaufmann SH, Poirier GG (2010) PARP inhibition: PARP1 and beyond. Nat Rev Cancer 10(4):293–301, Review
Ruf A, Mennissier de Murcia J, de Murcia G, Schulz GE (1996) Structure of the catalytic fragment of poly(AD-ribose) polymerase from chicken. Proc Natl Acad Sci USA 93:7481–7485
Russell JS, Brady K, Burgan WE et al (2003) Gleevec-mediated inhibition of Rad51 expression and enhancement of tumor cell radiosensitivity. Cancer Res 63:7377–7383
Sakai W et al (2008) Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 451:1116–1120
Saleh-Gohari N et al (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
Satoh MS, Poirier GG, Lindahl T (1994) Dual function for poly(ADP-ribose) synthesis in response to DNA strand breakage. Biochemistry 33:7099–7106
Schreiber V, Dantzer F, Ame JC, de Murcia G (2006) Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol 7(7):517–528, Review
Schwarze SR et al (2001) Role of cyclin-dependent kinase inhibitors in the growth arrest at senescence in human prostate epithelial and uroepithelial cells. Oncogene 20:8184–8192
Shen WH, Balajee AS, Wang J, Wu H, Eng C, Pandolfi PP et al (2007) Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 128:157–170
Slupianek A, Schmutte C, Tombline G et al (2001) BCR/ABL regulates mammalian RecA homologs, resulting in drug resistance. Mol Cell 8:795–806
Sonoda E, Hochegger H, Saberi A, Taniguchi Y, Takeda S (2006) Differential usage of non-homologous end-joining and homologous recombination in double strand break repair. DNA Repair (Amst) 5:1021–1029
Stein GH, Drullinger LF, Soulard A, Dulic V (1999) Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. Mol Cell Biol 19:2109–2117
Stewart GD, Ross JA, McLaren DB, Parker CC, Habib FK, Riddick AC (2010) The relevance of a hypoxic tumour microenvironment in prostate cancer. BJU Int 105:8–13
Stewart GD, Nanda J, Katz E, Bowman KJ, Christie JG, Brown DJ, McLaren DB, Riddick AC, Ross JA, Jones GD, Habib FK (2011) DNA strand breaks and hypoxia response inhibition mediate the radiosensitisation effect of nitric oxide donors on prostate cancer under varying oxygen conditions. Biochem Pharmacol 81(2):203–210
Takahashi S et al (1984) Enhancement of DEN initiation of liver carcinogenesis by inhibitors of NAD + ADP ribosyl transferase in rats. Carcinogenesis 5:901–906
Tannock IF, Hill RP, Bristow RG, Harrington L (2005) The basic science of oncology. McGraw-Hill Professional, New York
Timinszky G et al (2009) A macrodomain-containing histone rearranges chromatin upon sensing PARP1 activation. Nat Struct Mol Biol 16:923–929
Tong WM et al (2002) Synergistic role of Ku80 and poly(ADP-ribose) polymerase in suppressing chromosomal aberrations and liver cancer formation. Cancer Res 62:6990–6996
Tong WM et al (2003) Null mutation of DNA strand break-binding molecule poly(ADP-ribose) polymerase causes medulloblastomas in p53−/− mice. Am J Pathol 162:343–352
Trzeciak AR, Nyaga SG, Jaruga P, Lohani A, Dizdaroglu M, Evans MK (2004) Cellular repair of oxidatively induced DNA base lesions is defective in prostate cancer cell lines, PC-3 and DU-145. Carcinogenesis 25:1359–1370
Tulin A, Stewart D, Spradling AC (2002) The Drosophila heterochromatic gene encoding poly(ADP-ribose) polymerase (PARP) is required to modulate chromatin structure during development. Genes Dev 16:2108–2119
Tyson DR, Inokuchi J, Tsunoda T, Lau A, Ornstein DK (2007) Culture requirements of prostatic epithelial cell lines for acinar morphogenesis and lumen formation in vitro: role of extracellular calcium. Prostate 67:1601–1613
Vaupel P, Mayer A (2007) Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26:225–239
Venkitaraman AR (2002) Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108:171–182
Vukovic B, Park PC, Al-Maghrabi J et al (2003) Evidence of multifocality of telomere erosion in high-grade prostatic intraepithelial neoplasia (HPIN) and concurrent carcinoma. Oncogene 22:1978–1987
Ward JF (1988) DNA damage produced by ionizing radiation in mammalian cells: identities, mechanisms of formation, and reparability. Prog Nucleic Acid Res Mol Biol 35:95–125
Weterings E, van Gent DC (2004) The mechanism of non-homologous end-joining: a synopsis of synapsis. DNA Repair (Amst) 3:1425–1435
Willers H, Dahm-Daphi J et al (2004) Repair of radiation damage to DNA. Br J Cancer 90:1297–1301
Wong CS, Hill RP (1998) Experimental radiotherapy. In: Tannock IF, Hill RP (eds) The basic science of oncology, 3rd edn. McGraw-Hill, Toronto, pp 322–349
Wouters BG, Weppler SA, Koritzinsky M, Landuyt W, Nuyts S, Theys J, Chiu RK, Lambin P (2002) Hypoxia as a target for combined modality treatments. Eur J Cancer 38:240–257
Yuan R, Fan S, Wang JA et al (1999) Coordinate alterations in the expression of BRCA1, BRCA2, p300, and Rad51 in response to genotoxic and other stresses in human prostate cancer cells. Prostate 40:37–49
Zelefsky MJ, Chan H, Hunt M, Yamada Y, Shippy AM, Amols H (2006) Longterm outcome of high dose intensity modulated radiation therapy for patients with clinically localized prostate cancer. J Urol 176:1415–1419
Zong WX, Ditsworth D, Bauer DE, Wang ZQ, Thompson CB (2004) Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev 18:1272–1282
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Ilardi, G., Staibano, S. (2013). “Synthetic Lethality”: Molecular Co-targeting to Restore the DNA Repair Mechanisms in Prostate Cancer Cells. In: Staibano, S. (eds) Prostate Cancer: Shifting from Morphology to Biology. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7149-9_18
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