ABSTRACT Inhibition of histone deacetylases (HDACs) is emerging as a new strategy in cancer therapy. In the present work a novel pyrimido-quinoline benzene sulfonamide (PIQSA compound) was designed and synthesized postulating its ability to inhibit HDAC enzyme in cancer cells. This study was designed to examine the in vitro anti-tumor efficacy of PIQSA against Ehrlich Ascite carcinoma cells (EAC) and three of the human cancer cell lines (H460), brain (U251) and liver (HepG2). The results of Cytotoxic assays showed that PIQSA exhibited in vitro antitumor activity in a dose dependant manner. The tumor growth delay studies indicating that PIQSA resulted in significant regression in tumor growth, which was more pronounced when PIQSA treatment accompanied with radiation exposure. Also, the efficacy of PIQSA to influence radiation response in Ehrlich solid carcinoma (ESC) tumors was estimated. The results suggest that PIQSA exhibited antitumor activities and strong radioenhancing properties associated with inhibition of HDAC activity, DNA fragmentation followed by apoptotic cell death, preferential cell loss of cells particularly in G1/G0 phase through an apoptotic pathway.
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nullE. Noaman, N. Fahmy, R. Yousri, O. Shawi and M. Ghazy, "Evaluation of the Antitumor and Radiosynthetizing Activity of a Novel Quinoline Sulfonamide Derivative (PIQSA) as a Histone Deacetylase Inhibitor," Journal of Cancer Therapy, Vol. 2 No. 4, 2011, pp. 567-578. doi: 10.4236/jct.2011.24077.
 G. J. Kellof, “Perspective on Cancer Chemoprevention Research and Drug Development,” Advances in Cancer Research, Vol. 78, 1999, pp. 199-334.
 M. El-Gaby, S. Abdel Gawad, M. Ghorab, et al., “Synthesis and Biological Activity of Some Novel Thieno[2,3-d]quinpline, Quinoline[3,2:4,5]thieno[3,2-d]pyrimidine and Pyrido[2,3:4,5]thieno[2,3-d]quinoline Derivatives,” Phosphorus, Sulphur, Silicon and Related Elements, Vol. 181, No. 2, 2006, pp. 279-297.
 V. V. Kouznetsov, C. O. Puentes, A. R. R. Bohorques, S. A. Zacchino, M. Sortino, M. Gupta, et al., “A Straightforward Synthetic Approach to Antitumoral Pyridinyl Substituted 7H-Indino [2,1-C] Quinoline Derivatives via Three-Component Imino Diels-Alder Reaction,” Letters in Organic Chemistry, Vol. 3, No. 4, 2006, pp. 300-304.
 G. Bouchain, S. Leit, S. Frechette, E. A. Khalil, R. Lavoie, O. Moradei, S. H. Woo, M. Fournel. P. T. Yan, A. Kalita, M. C. Trachy-Bourget, C. Beaulieu, M. F. Robert, A. R. MacLeod, J. M. Besterman and D. Delorme, “Development of Potential Antitumor Agents. Synthesis and Biological Evaluation of a New Set of Sulfonamide Derivatives as Histone Deacetylase Inhibitors,” Journal of Medicinal Chemistry, Vol. 46, No. 5, 2003, pp. 820-830.
 P. W. Finn, M. Bandara, C. Butcher, A. Finn, R. Hollinshead, N. Khan, N. Law, S. Murthy, R. Romero and C. Watkins, “Novel Sulfonamide Derivatives as Inhibitors of Histone Deacetylase,” Helvetica Chimica Acta, Vol. 88, No. 7, 2005, pp. 1630-1657. doi:10.1002/hlca.200590129
 M. M. Ghorab, F. A. Ragab, E. Noaman, H. I. Heiba and E. M. El-Hossary, “Synthesis of Some Novel Quinolines and Pyrimido [4,5-B] Quinolines Bearing a Sulfonamide Moiety as Potential Anticancer and Radioprotective Agents,” Arzneimittelforschung, Vol. 57, No. 12, 2007, pp. 795-803.
 L. Hu, Z. R. Li, J. D. Jiang and D. W. Boykin, “Novel Diaryl or Heterocyclic Sulfonamides as Antimitotic Agents. Anti-Cancer Agents in Medicinal Chemistry,” Anti-Cancer Agents in Medicinal Chemistry, Vol. 8, No. 7, 2008, pp. 739-745.
 M. Fournel, M. C. Trachy-Bourget, P. T. Yan, A. Kalita, C. Bonfils, C. Beaulieu, S. Frechette, S. Leit, E. Abou-Khalil, S. H. Woo, D. Delorme, A. R. MacLeod, J. M. Besterman and Z. Li, “Sulfonamide Anilides, a Novel Class of Histone Deacetylase Inhibitors, Are Antiproliferative against Human Tumors,” Cancer Research, Vol. 62, No. 15, 2002, pp. 4325-4330.
 K. B. Glaser, M. J. Staver, J. F. Waring, J. Stender, R. G. Ulrich and S. K. Davidsen, “Gene Expression Profiling of Multiple Histone Deacetylase (HDAC) Inhibitors: Defining a Common Gene Set Produced by HDAC Inhibition in T24 and MDA Carcinoma Cell Lines,” Molecular Cancer Therapeutics, Vol. 2, No. 2, 2003, pp. 151-163.
 L. C. Hsi, X. Xi, R. Lotan, I. Shureiqi and S. M. Lippman, “The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Induces Apoptosis via Induction of 15-lipoxygenase-1 in Colorectal Cancer Cells,” Cancer Research, Vol. 64, No. 23, 2004, pp. 8778-8781.
 P. Peixoto and A. Lansiaux, “Histone-Deacetylases Inhibitors: From TSA to SAHA,” Bull Cancer, Vol. 93, No. 1, 2006, pp. 27-36.
 S. Sakajiri, T. Kumagai, N. Kawamata, T. Saitoh, J. W. Said and H. P. Koeffler, “Histone Deacetylase Inhibitors Profoundly Decrease Proliferation of Human Lymphoid Cancer Cell Lines,” Experimental Hematology, Vol. 33, No. 1, 2005, pp. 53-61.
 C. Zhang, V. Richon, X. Ni, R. Talpur and M. Duvic, “Selective Induction of Apoptosis by Histone Deacetylase Inhibitor SAHA in Cutaneous T-Cell Lymphoma Cells: Relevance to Mechanism of Therapeutic Action,” Journal of Investigative Dermatology, Vol. 125, No. 5, 2005, pp. 1045-1052. doi:10.1111/j.0022-202X.2005.23925.x
 H. Choy and L. Milas, “Enhancing Radiotherapy with Cyclooxygenase-2 Enzyme Inhibitors: A Rational Advance?” Journal of the National Cancer Institute, Vol. 95, No. 19, 2003, pp. 1440-1452.
 M. Entin-Meer, X. Yang, S. R. V. Berg, K. R. Lamborn, A. Nudelman, A. Rephaeli and D. A. Haas-Kogan, “In Vivo Efficacy of a novel Histone Deacetylase Inhibitor in Combination with Radiation for the Treatment of Gliomas,” Neuro-Oncology, Vol. 9, No. 2, 2007, pp. 82-88.
 M. Entin-Meer, A. Rephaeli, X. Yang, A. Nudelman, S. R. Vandenberg and D. A. Haas-Kogan, “Butyric Acid Prodrugs Are Histone Deacetylase Inhibitors That Show Antineoplastic Activity and Radiosensitizing Capacity in the Treatment of Malignant Gliomas,” Molecular Cancer Therapeutics, Vol. 4, No. 12, 2005, pp. 1952-1961.
 K. Camphausen, D. Cerna, T. Scott, M. Sproull, W. E. Burgan, M. A. Cerra, H. Fine and P. J. Tofilon, “Enhancement of in Vitro and in Vivo Tumor Cell Radiosensitivity by Valproic Acid,” International Journal of Cancer, Vol. 114, No. 3, 2005, pp. 380-386.
 A. Munshi, J. F. Kurland, T. Nishikawa, T. Tanaka, M. L. Hobbs, S. L. Tucker, S. Ismail, C. Stevens and R. E. Meyn, “Histone Deacetylase Inhibitors Radiosensitize Human Melanoma Cells by Suppressing DNA Repair Activity,” Clinical Cancer Research, Vol. 11, 2005, pp. 4912-4922. doi:10.1158/1078-0432.CCR-04-2088
 Y. Zhang, M. Jung, A. Dritschilo and M. Jung, “Enhancement of Radiation Sensitivity of Human Squamous Carcinoma Cells by Histone Deacetylase Inhibitors,” Radiation Research, Vol. 161, No. 916, 2004, pp. 667-674.
 M. Gupta, U. K. Mazumder, R. S. Kumar and T. S. Kumar, “Antitumor Activity and Antioxidant Role of Bauhinia Racemosa against Ehrlich Ascites Carcinoma in Swiss Albino Mice,” Acta Pharmacologica Sinica, Vol. 25, No. 8, 2004, pp. 1070-1076.
 F. M. Freimoser, C. A. Jakob, M. Aebi and U. Tuor, “The MTT [3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide] Assay Is a Fast and Reliable Method for Colorimetric Determination of Fungal Cell Densities,” Applied and Environmental Microbiology, Vol. 65, No. 8, 1999, pp. 3727-3729.
 M. M. Jones, J. E. Schoenheit and A. D. Weaver, “Retreatment and Heavy Metal LD50 Values,” Toxicology and Applied Pharmacology, Vol. 49, No. 1, 1979, pp. 41-44. doi:10.1016/0041-008X(79)90274-6
 J. A. Nagle, Z. Ma, M. A. Byrne, M. F. White and L. M. Shaw, “Involvement of Insulin Receptor Substrate 2 in Mammary Tumor Metastasis,” Molecular and Cellular Biology, Vol. 24, No. 22, 2004, pp. 9726-9735.
 D. Baidyaroy, G. Brosch, S. Graessle, P. Trojer and J. D. Walton, “Characterization of Inhibitor-Resistant Histone Deacetylase Activity in Plant-Pathogenic Fungi,” Eukaryotic Cell, Vol. 1, No. 4, 2002, pp. 538-547.
 B. D. Strahl and C. D. Allis, “The Language of Covalent Histone Modifications,” Nature, Vol. 403, 2000, pp. 41-45. doi:10.1038/47412
 P. Salgame, S. V. Arun, L. L. Primiano, J. E. Fincke, M. Sylviane and M. Monestier, “An ELISA for Detection of Apoptosis,” Oxford University Press, 1997, pp. 680-681.
 B. B. Mishell, S. M. Shiiqi, C. Henry, E. L. Chen, J. North, R. Gallily, M. Slomich, K. Miller, J. Marbrook, D. Parks and A. H. Good, “Selected Methods in Cellular Immunology,” W. H. Freeman, San Francisco, 1980, pp. 21-22.
 Y. H. Choi, L. Zhang, W. H. Lee and K. Y. Park, “Genistein-Induced G2/M Arrest Is Associated with the Inhibition of Cyclin B1 and the Induction of p21 in Human Breast Carcinoma Cells,” International Journal of Oncology, Vol. 13, No. 2, 1998, pp. 391-396.
 R. G. Steel, and T. H. Torrie, “Principles and Procedures of Statistics,” 2nd Edition, McCraw-Hill Book Co., New York, 1980.
 S. E. Touma, J. S. Goldberg, P. Moench, et al., “Retinoic Acid and the Histone Deacetylase Inhibitor Trichostatin a Inhibit the Proliferation of Human Renal Cell Carcinoma in a Xenograft Tumor Model,” Clinical Cancer Research, Vol. 11, No. 9, 2005, pp. 3558-3662.
 D. Z. Qian, X. Wang, S. K. Kachhap, et al., “The Histone Deacetylase Inhibitor NVP-LAQ824 Inhibits Angiogenesis and Has a Greater Antitumor Effect in Combination With the Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor,” Cancer Research, Vol. 64, No. 18, 2004, pp. 6626-6634.
 K. Camphausen, T. Scott, M. Sproull and P. J. Tofilon, “Enhancement of Xenograft Tumor Radiosensitivity by the Histone Deacetylase Inhibitor MS-275 and Correlation with Histone Hyperacetylation,” Clinical Cancer Research, Vol. 10, 2004, pp. 6066-6071.
 J. A. Plumb, P. W. Finn, R. J. Williams, et al., “Pharmacodynamic Response and Inhibition of Growth of Human Tumor Xenografts by the Novel Histone Deacetylase Inhibitor PXD101,” Molecular Cancer Therapeutics, Vol. 2, No. 8, 2003, pp. 721-728.
 Y. Komatsu, K. Y. Tomizaki, M. Tsukamoto, et al., “Cyclic Hydroxamicacid-Containing Peptide 31, a Potent Synthetic Histone Deacetylase Inhibitor with Antitumor Activity,” Cancer Research, Vol. 61, 2001, pp. 4459-4466.
 N. Takai, J. C. Desmond, T. Kumagai, et al., “Histone Deacetylase Inhibitors Have a Profound Antigrowth Activity in Endometrial Cancer Cells,” Clinical Cancer Research, Vol. 10, 2004, pp. 1141-1149.
 J. J. Buggy, Z. A. Cao, K. E. Bass and E. Verner, “CRA-024781: A Novel Synthetic Inhibitor of Histone Deacetylase Enzymes with Antitumor Activity in Vitro and in Vivo,” Molecular Cancer Therapeutics, Vol. 5, 2006, pp. 1309-1317. doi:10.1158/1535-7163.MCT-05-0442
 P. Rocchi, C. Camerin, S. Purgato, R. Fronza, F. Bianucci, F. Guerra, A. Pession and A. M. Ferreri, “p21Waf1/Cip1 Is a Common Target Induced by Short-Chain Fatty Acid HDAC Inhibitors (Valproic Acid, Tributyrin and Sodium Butyrate) in Neuroblastoma Cells,” Oncology Reports, Vol. 13, No. 6, 2005, pp. 1139-1144.
 N. K. Mukhopadhyay, E. Weisberg, D. Gilchrist, R. Bueno, D. J. Sugarbaker and M. T. Jaklitsch, “Effectiveness of Trichostatin A as a Potential Candidate for Anticancer Therapy in Non-Small-Cell Lung Cancer,” The Annals of Thoracic Surgery, Vol. 81, No. 3, 2006, pp. 1034-1042. doi:10.1016/j.athoracsur.2005.06.059
 R. S. Kumar, B. Jayakar and B. Rajkapoor, “Antitumor Activity of Indigofera Trita on Ehrlich Ascites Carcinoma Induced Mice,” International Journal of Cancer Research, Vol. 3, No. 4, 2007, pp. 180-185.
 P. Gallinari, S. Di Marco, P. Jones, M. Pallaoro and C. Steinkuhler, “HDACs, Histone Deacetylation and Gene Transcription: From Molecular Biology to Cancer Therapeutics,” Cell Research, Vol. 17, No. 3, 2007, pp. 195-211.
 V. Baradari, A. Huether, M. Hopfner, D. Schuppan and H. Scherubl, “Antiproliferative and Proapoptotic Effects of Histone Deacetylase Inhibitors on Gastrointestinal Neuroendocrine Tumor Cells,” Endocrine-Related Cancer, Vol. 13, No. 4, 2006, pp. 1237-1250.
 C. J. Phiel, F. Zhang, E. Y. Huang, M. G. Guenther, M. A. Lazar and P. S. Klein, “Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen,” Journal of Biological Chemistry, Vol. 276, No. 39, 2001, pp. 36734-36741.
 C. Monneret, “Histone Deacetylase Inhibitors,” European Journal of Medicinal Chemistry, Vol. 40, No. 1, 2005, pp. 1-13. doi:10.1016/j.ejmech.2004.10.001
 M. C. Myzak and R. H. Dashwood, “Histone Deacetylases as Targets for Dietary Cancer Preventive Agents: Lessons Learned with Butyrate, Diallyl Disulfide, and Sulforaphane,” Current Drug Targets, Vol. 7, No. 4, 2006, pp. 443-452. doi:10.2174/138945006776359467
 M. S. Finnin, J. R. Donigian, A. Cohen, V. M. Richon, R. A. Rifkind, P. A. Marks, R. Breslow and N. P. Pavletich, “Structures of a Histone Deacstylase Homologue Bound to the TSA and SAHA Inhibitors,” Nature, Vol. 401, 1999, pp. 188-193. doi:10.1038/43710
 A. H. Wyllie, J. F. R. Kerr and A. R. Currie, “Cell Death: The Significance of Apoptosis,” International Review of Cytology, Vol. 68, 1980, pp. 251-306.
 X. Liu, P. Li, P. Widlak, H. Zou, X. Luo, W. T. Garrard and X. Wang, “The 40-kDa Subunit of DNA Fragmentation Factor Induces DNA Fragmentation and Chromatin Condensation during Apoptosis,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 95, No. 925, 1998, pp. 8461-8466.
 M. Enari, H. Sakahira, H. Yokoyama, K. Okawa, A. Iwamatsu and S. Nagata, “A Caspase-Activated DNase that Degrades DNA during Apoptosis, and Its Inhibitor ICAD,” Nature, Vol. 391, 1998, pp. 43-50.
 D. A. Hsia, S. K. Mitra, C. R. Hauck, D. N. Streblow, J. A. Nelson, D. Ilic, S. Huang, E. Li, G. R. Nemerow, J. Leng, K. S. Spencer, D. A. Cheresh and D. D. Schlaepfer, “Differential Regulation of Cell Motility and Invasion by FAK,” Journal of Cell Biology, Vol. 160, No. 5, 2003, pp. 753-767.
 F. Abel, R. M. Sjoberg, C. Krona, S. Nilsson and T. Martinsson, “Mutations in the N-Terminal Domain of DFF45 in a Primary Germ Cell Tumor and in Neuroblastoma Tumors,” International Journal of Oncology, Vol. 25, No. 5, 2004, pp. 1297-1302.
 G. Driessens, L. Harsan, P. Browaeys, X. Giannakopoulos, T. Velu and C. Bruyns, “Assessment of in Vivo Chemotherapy-Induced DNA Damage in a p53-Mutated Rat Tumor by Micronuclei Assay,” Annals of the New York Academy of Sciences, Vol. 1010, 2003, pp. 775-779.
 P. Widlak, J. Lanuszewska, R. B. Cary and W. T. Garrard, “Subunit Structures and Stoichiometries of Human DFF Proteins before and after Induction of Apoptosis,” Journal of Biological Chemistry, Vol. 278, No. 29, 2003, pp. 26915-26922. doi:10.1074/jbc.M303807200
 H. Kamitani, S. Taniura, K. Watanabe, M. Sakamoto, T. Watanabe and T. Eling, “Histone Acetylation May Suppress Human Glioma Cell Proliferation When p21WAF/ Cip1 and Gelsolin Are Induced,” Neuro Oncology, Vol. 4, 2002, pp. 95-101.
 K. Suzuki, M. Ojima, S. Kodama and M. Watanabe, “Radiation Induced DNA Damage and Delayed Induced Genomic Instability,” Oncogene, Vol. 2, 2003, pp. 6988-6993. doi:10.1038/sj.onc.1206881
 Y. Higuchi, “Chromosomal DNA Fragmentation in Apoptosis and Necrosis Induced by Oxidative Stress,” Biochemical Pharmacology, Vol. 66, No. 8, 2003, pp. 1527-1535. doi:10.1016/S0006-2952(03)00508-2
 K. Bhalla and A. List, “Histone Deacetylase Inhibitors in Myelodysplastic Syndrome,” Best Practice & Research Clinical Haematology, Vol. 17, 2004, pp. 595-611.
 J. L. Aron, M. R. Parthun, G. Marcucci, S. Kitada, A. P. Mone, M. E. Davis, T. Shen, T. Murphy, J. Wickham, C. Kanakry, D. M. Lucas, J. C. Reed, M. R. Grever and J. C. Byrd, “Depsipeptide (FR901228) Induces Histone Acetylation and Inhibition of Histone Deacetylase in Chronic Lymphocytic Leukaemia Cells Concurrent with Activation of Caspase 8-Mediated Apoptosis and Down-Regulation of C-FLIP Protein,” Blood, Vol. 102, No. 2, 2003, pp. 652-658. doi:10.1182/blood-2002-12-3794
 F. Guo, C. Sigua, J. Tao, P. Bali, P. George, Y. Li, S. Wittmann, L. Moscinski, P. Atadja and K. Bhalla, “Cotreatment with Histone Deacetylase Inhibitor LAQ824 Enhances Apo-2l/Tumor Necrosis Factor-Related Apoptosis Inducing Ligand-Induced Death Inducing Signaling Complex Activity and Apoptosis of Human Acute Leukemia Cells,” Cancer Research, Vol. 64, 2004, pp. 2580-2589. doi:10.1158/0008-5472.CAN-03-2629
 R. R. Rosato, J. A. Almenara and S. Grant, “The Histone Deacetylase Inhibitor MS-275 Promotes Differentiation or Apoptosis in Human Leukemia Cells through a Process Regulated by Generation of Reactive Oxygen Species and Induction of p21CIP1/WAF1,” Cancer Research, Vol. 63, 2003, pp. 3637-3645.
 E. S. Arner and A. Holmgren, “Physiological Functions of Thioredoxin and Thioredoxin Reductase,” European Journal of Biochemistry, Vol. 267, No. 20, 2000, pp. 6102-6109. doi:10.1046/j.1432-1327.2000.01701.x
 S. Y. Archer, J. Johnson, H. J. Kim, Q. Ma, H. Mou, V. Daesety, S. Meng and R. A. Hodin, “The Histone Deacetylase Inhibitor Butyrate Down Regulates Cyclin B1 Gene Expression via a p21/WAF-1-Dependent Mechanism in Human Colon Cancer Cells,” American Journal of Physiology—Gastrointestinal and Liver Physiology, Vol. 289, No. 4, 2005, pp. 696-703.
 Y. X. Chen, J. Y. Fang, J. Lu and D. K. Qiu, “Regulation of Histone Acetylation on the Expression of Cell Cycle-Associated Genes in Human Colon Cancer Cell Lines,” Chinese Medical Journal, Vol. 84, No. 4, 2004, pp. 312-317.
 A. Adamczyk and A. Gasinska, “The Influence of Fractionated Radiation on Proliferation, Cell Cycle and Apoptosis of Normal Human Dermal Fibroblasts,” Nukleonika, Vol. 50, No. 2, 2005, pp. 9-12.
 L. Geng, K. C. Cuneo, A. Fu, T. Tu, P. W. Atadja and D. E. Hallahan, “Histone Deacetylase (HDAC) Inhibitor LBH589 Increases Duration of γ-H2AX Foci and Confines HDAC4 to the Cytoplasm in Irradiated Non–Small Cell Lung Cancer,” Cancer Research, Vol. 66, No. 23, 2006, p. 11298. doi:10.1158/0008-5472.CAN-06-0049
 I. A. Kim, J. H. Shin, Il H. Kim, J. H. Kim, J. S. Kim, H. G. Wu, E. K. Chi, S. W. Ha, C. I. Park and G. D. Kao, “Histone Deacetylase Hong Gyun Wu, Inhibitor Mediated Radio Sensitization of Human Cancer Cells: Class Differences and the Potential Influence of p53,” Clinical Cancer Research, Vol. 12, No. 3, 2006, p. 940.
 K. Camphausen, W. Burgan, M. Cerra, K. A. Oswald, J. B. Trepel, M. J. Lee and P. J. Tofilon. “Enhanced Radiationinduced Cell Killing and Prolongation of γH2AX Foci Expression by the Histone Deacetylase Inhibitor MS-275,” Cancer Research, Vol. 64, 2004, pp. 316-321.
 J. Luo, F. Su, D. Chen, A. Shiloh and W. Gu, “Deacetylation of p53 Modulates Its Effect on Cell Growth and Apoptosis,” Nature, Vol. 408, 2000, pp. 377-381.
 J. Joseph, N. Wajapeyee and K. Somasundaram, “Role of p53 Status in Chemosensitivity Determination of Cancer Cells against Histone Deacetylase Inhibitor Sodium Butyrate,” International Journal of Cancer, Vol. 115, No. 1, 2005, pp. 11-18. doi:10.1002/ijc.20842
 A. Eastman, “Cell Cycle Checkpoints and Their Impact on Anticancer Therapeutic Strategies,” Journal of Cellular Biochemistry, Vol. 91, 2004, pp. 223-231.
 S. J. Collis, M. J. Swartz, W. G. Nelson and T. L. DeWeese, “Enhanced Radiation and Chemotherapy-Mediated Cell Killing of Human Cancer Cells by Small Inhibitory RNA Silencing of DNA Repair Factors,” Cancer Research, Vol. 63, 2003, pp. 1550-1554.
 S. P. Jackson, “Sensing and Repairing DNA Double-Strand Breaks,” Carcinogenesis, Vol. 23, No. 5, 2002, pp. 687-696. doi:10.1093/carcin/23.5.687
 S. Omori, Y. Takiguchi, A. Suda, T. Sugimoto, H. Miyazawa, Y. Takiguchi, N. Tanabe, K. Tatsumi, H. Kimura, P. E. Pardington, F. Chen, D. J. Chen and T. Kuriyama, “Suppression of a DNA Doublestrand Break Repair Gene, Ku70, Increases Radio- and Chemosensitivity in a Human Lung Carcinoma Cell Line,” DNA Repair, Vol. 1, No. 4, 2002, pp. 299-310. doi:10.1016/S1568-7864(02)00006-X
 E. Marangoni, N. Foray, M. O’Driscoll, S. Douc-Rasy, J. Bernier, J. Bourhis, P. Jeggo, “A Ku80 Fragment with Dominant Negative Activity Imparts a Radiosensitive Phenotype to CHO-K1 Cells,” Nucleic Acids Research, Vol. 28, 2000, pp. 4778-4782.