@article {7067,
	title = {DNA repair of myeloma plasma cells correlates with clinical outcome: The effect of the nonhomologous end-joining inhibitor SCR7},
	journal = {Blood},
	volume = {128},
	year = {2016},
	note = {Export Date: 18 February 2017References: Chng, W.J., Glebov, O., Bergsagel, P.L., Kuehl, W.M., Genetic events in the pathogenesis of multiple myeloma (2007) Best Pract Res Clin Haematol, 20 (4), pp. 571-596;Anderson, K.C., Carrasco, R.D., Pathogenesis of myeloma (2011) Annu Rev Pathol, 6, pp. 249-274; 
Giralt, S., 200 mg/m2 melphalan-The gold standard for multiple myeloma (2010) Nat Rev Clin Oncol, 7 (9), pp. 490-491; 
Cavo, M., Rajkumar, S.V., Palumbo, A., International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation (2011) Blood, 117 (23), pp. 6063-6073; 
San Miguel, J.F., Schlag, R., Khuageva, N.K., Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma (2008) N Engl J Med, 359 (9), pp. 906-917; 
Redic, K., Carfilzomib: A novel agent for multiple myeloma (2013) J Pharm Pharmacol, 65 (8), pp. 1095-1106; 
Anderson, K.C., The 39th David A. Karnofsky Lecture: Bench-to-bedside translation of targeted therapies in multiple myeloma (2012) J Clin Oncol, 30 (4), pp. 445-452; 
Kumar, S.K., Lee, J.H., Lahuerta, J.J., Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: A multicenter international myeloma working group study (2012) Leukemia, 26 (1), pp. 149-157; 
Genadieva-Stavric, S., Cavallo, F., Palumbo, A., New approaches to management of multiple myeloma (2014) Curr Treat Options Oncol, 15 (2), pp. 157-170; 
Edler, M., Jakubowski, N., Linscheid, M., Quantitative determination of melphalan DNA adducts using HPLC - Inductively coupled mass spectrometry (2006) J Mass Spectrom, 41 (4), pp. 507-516; 
Dronkert, M.L., Kanaar, R., Repair of DNA interstrand cross-links (2001) Mutat Res, 486 (4), pp. 217-247; 
Episkopou, H., Kyrtopoulos, S.A., Sfikakis, P.P., Association between transcriptional activity, local chromatin structure, and the efficiencies of both subpathways of nucleotide excision repair of melphalan adducts (2009) Cancer Res, 69 (10), pp. 4424-4433; 
Thompson, L.H., Hinz, J.M., Cellular and molecular consequences of defective Fanconi anemia proteins in replication-coupled DNA repair: Mechanistic insights (2009) Mutat Res, 668 (1-2), pp. 54-72; 
Deans, A.J., West, S.C., DNA interstrand crosslink repair and cancer (2011) Nat Rev Cancer, 11 (7), pp. 467-480; 
Hanlon Newell, A.E., Hemphill, A., Akkari, Y.M., Hejna, J., Moses, R.E., Olson, S.B., Loss of homologous recombination or non-homologous end-joining leads to radial formation following DNA interstrand crosslink damage (2008) Cytogenet Genome Res, 121 (3-4), pp. 174-180; 
Gorrini, C., Harris, I.S., Mak, T.W., Modulation of oxidative stress as an anticancer strategy (2013) Nat Rev Drug Discov, 12 (12), pp. 931-947; 
Simonelli, V., Narciso, L., Dogliotti, E., Fortini, P., Base excision repair intermediates are mutagenic in mammalian cells (2005) Nucleic Acids Res, 33 (14), pp. 4404-4411; 
Bee, L., Fabris, S., Cherubini, R., Mognato, M., Celotti, L., The efficiency of homologous recombination and non-homologous end joining systems in repairing double-strand breaks during cell cycle progression (2013) PLoS One, 8 (7); 
Chernikova, S.B., Game, J.C., Brown, J.M., Inhibiting homologous recombination for cancer therapy (2012) Cancer Biol Ther, 13 (2), pp. 61-68; 
Kuo, L.J., Yang, L.X., Gamma-H2AX - A novel biomarker for DNA double-strand breaks (2008) In Vivo, 22 (3), pp. 305-309; 
Clingen, P.H., Wu, J.Y., Miller, J., Histone H2AX phosphorylation as a molecular pharmacological marker for DNA interstrand crosslink cancer chemotherapy (2008) Biochem Pharmacol, 76 (1), pp. 19-27; 
Stefanou, D.T., Bamias, A., Episkopou, H., Aberrant DNA damage response pathways may predict the outcome of platinum chemotherapy in ovarian cancer (2015) PLoS One, 10 (2); 
Souliotis, V.L., Sfikakis, P.P., Increased DNA doublestrand breaks and enhanced apoptosis in patients with lupus nephritis (2015) Lupus, 24 (8), pp. 804-815; 
Plummer, R., Perspective on the pipeline of drugs being developed with modulation of DNA damage as a target (2010) Clin Cancer Res, 16 (18), pp. 4527-4531; 
Lord, C.J., Ashworth, A., The DNA damage response and cancer therapy (2012) Nature, 481 (7381), pp. 287-294; 
Smith, J., Tho, L.M., Xu, N., Gillespie, D.A., The ATMChk2 and ATR-Chk1 pathways in DNA damage signaling and cancer (2010) Adv Cancer Res, 108, pp. 73-112; 
Pei, X.-Y., Dai, Y., Youssefian, L.E., Cytokinetically quiescent (G0/G1) human multiple myeloma cells are susceptible to simultaneous inhibition of Chk1 and MEK1/2 (2011) Blood, 118 (19), pp. 5189-5200; 
Sousa, M.M., Zub, K.A., Aas, P.A., An inverse switch in DNA base excision and strand break repair contributes to melphalan resistance in multiple myeloma cells (2013) PLoS One, 8 (2); 
Deriano, L., Guipaud, O., Merle-B{\'e}ral, H., Human chronic lymphocytic leukemia B cells can escape DNA damage-induced apoptosis through the nonhomologous end-joining DNA repair pathway (2005) Blood, 105 (12), pp. 4776-4783; 
Willmore, E., De Caux, S., Sunter, N.J., A novel DNA-dependent protein kinase inhibitor, NU7026, potentiates the cytotoxicity of topoisomerase II poisons used in the treatment of leukemia (2004) Blood, 103 (12), pp. 4659-4665; 
Greipp, P.R., San Miguel, J., Durie, B.G., International staging system for multiple myeloma (2005) J Clin Oncol, 23 (15), pp. 3412-3420; 
Durie, B.G., Harousseau, J.L., Miguel, J.S., International uniform response criteria for multiple myeloma (2006) Leukemia, 20 (9), pp. 1467-1473; 
Stefanou, D.T., Episkopou, H., Kyrtopoulos, S.A., Development and validation of a PCR-based assay for the selection of patients more likely to benefit from therapeutic treatment with alkylating drugs (2012) Br J Clin Pharmacol, 74 (5), pp. 842-853; 
Souliotis, V.L., Dimopoulos, M.A., Episkopou, H.G., Kyrtopoulos, S.A., Sfikakis, P.P., Preferential in vivo DNA repair of melphalan-induced damage in human genes is greatly affected by the local chromatin structure (2006) DNA Repair (Amst), 5 (8), pp. 972-985; 
Episkopou, H., Kyrtopoulos, S.A., Sfikakis, P.P., Dimopoulos, M.A., Souliotis, V.L., The repair of melphalan-induced DNA adducts in the transcribed strand of active genes is subject to a strong polarity effect (2011) Mutat Res, 714 (1-2), pp. 78-87; 
Gkotzamanidou, M., Terpos, E., Bamia, C., Progressive changes in chromatin structure and DNA damage response signals in bone marrow and peripheral blood during myelomagenesis (2014) Leukemia, 28 (5), pp. 1113-1121; 
Avramis, I.A., Christodoulopoulos, G., Suzuki, A., In vitro and in vivo evaluations of the tyrosine kinase inhibitor NSC 680410 against human leukemia and glioblastoma cell lines (2002) Cancer Chemother Pharmacol, 50 (6), pp. 479-489; 
Bellamy, W.T., Dalton, W.S., Gleason, M.C., Grogan, T.M., Trent, J.M., Development and characterization of a melphalan-resistant human multiple myeloma cell line (1991) Cancer Res, 51 (3), pp. 995-1002; 
Stronach, E.A., Chen, M., Maginn, E.N., DNA-PK mediates AKT activation and apoptosis inhibition in clinically acquired platinum resistance (2011) Neoplasia, 13 (11), pp. 1069-1080; 
Amrein, L., Loignon, M., Goulet, A.C., Chlorambucil cytotoxicity in malignant B lymphocytes is synergistically increased by 2-(morpholin-4-yl)-benzo[h]chomen-4-one (NU7026)-mediated inhibition of DNA doublestrand break repair via inhibition of DNAdependent protein kinase (2007) J Pharmacol Exp Ther, 321 (3), pp. 848-855; 
Srivastava, M., Nambiar, M., Sharma, S., An inhibitor of nonhomologous end-joining abrogates double-strand break repair and impedes cancer progression (2012) Cell, 151 (7), pp. 1474-1487; 
Budke, B., Logan, H.L., Kalin, J.H., RI-1: A chemical inhibitor of RAD51 that disrupts homologous recombination in human cells (2012) Nucleic Acids Res, 40 (15), pp. 7347-7357; 
Gkotzamanidou, M., Sfikakis, P.P., Kyrtopoulos, S.A., Bamia, C., Dimopoulos, M.A., Souliotis, V.L., Chromatin structure, transcriptional activity and DNA repair efficiency affect the outcome of chemotherapy in multiple myeloma (2014) Br J Cancer, 111 (7), pp. 1293-1304; 
Souliotis, V.L., Dimopoulos, M.A., Sfikakis, P.P., Gene-specific formation and repair of DNA monoadducts and interstrand cross-links after therapeutic exposure to nitrogen mustards (2003) Clin Cancer Res, 9 (12), pp. 4465-4474; 
Li, Y.H., Wang, X., Pan, Y., Lee, D.H., Chowdhury, D., Kimmelman, A.C., Inhibition of non-homologous end joining repair impairs pancreatic cancer growth and enhances radiation response (2012) PLoS One, 7 (6); 
Spanswick, V.J., Craddock, C., Sekhar, M., Repair of DNA interstrand crosslinks as a mechanism of clinical resistance to melphalan in multiple myeloma (2002) Blood, 100 (1), pp. 224-229; 
Dimopoulos, M.A., Souliotis, V.L., Anagnostopoulos, A., Papadimitriou, C., Sfikakis, P.P., Extent of damage and repair in the p53 tumor-suppressor gene after treatment of myeloma patients with high-dose melphalan and autologous blood stemcell transplantation is individualized and may predict clinical outcome (2005) J Clin Oncol, 23 (19), pp. 4381-4389; 
Dimopoulos, M.A., Souliotis, V.L., Anagnostopoulos, A., Melphalan-induced DNA damage in vitro as a predictor for clinical outcome in multiple myeloma (2007) Haematologica, 92 (11), pp. 1505-1512; 
Gong, F., Kwon, Y., Smerdon, M.J., Nucleotide excision repair in chromatin and the right of entry (2005) DNA Repair (Amst), 4 (8), pp. 884-896; 
Lehmann, A.R., Niimi, A., Ogi, T., Translesion synthesis: Y-family polymerases and the polymerase switch (2007) DNA Repair (Amst), 6 (7), pp. 891-899; 
Hanada, K., Budzowska, M., Modesti, M., The structure-specific endonuclease Mus81-Eme1 promotes conversion of interstrand DNA crosslinks into double-strands breaks (2006) EMBO J, 25 (20), pp. 4921-4932; 
Buis, J., Wu, Y., Deng, Y., Mre11 nuclease activity has essential roles in DNA repair and genomic stability distinct from ATM activation (2008) Cell, 135 (1), pp. 85-96; 
Helleday, T., Lo, J., Van Gent, D.C., Engelward, B.P., DNA double-strand break repair: From mechanistic understanding to cancer treatment (2007) DNA Repair (Amst), 6 (7), pp. 923-935
},
	month = {2016},
	pages = {1214 - 1225},
	abstract = {DNA repair activity of malignant cells seems to influence therapeutic outcome and patients{\textquoteright} survival. Herein, we investigated the mechanistic basis for the link between DNA repair efficiency and response to antimyeloma therapy. Nucleotide excision repair (NER), interstrand cross-links repair (ICL/R), double-strand breaks repair (DSB/R), and chromatin structure were evaluated in multiple myeloma (MM) cell lines (melphalan-sensitive RPMI8226; melphalan-resistant LR5) and bone marrow plasma cells (BMPCs) from MM patients who responded (n = 17) or did not respond (n = 9) to subsequent melphalan therapy. The effect of DSB/R inhibition was also evaluated. Responders{\textquoteright} BMPCs showed slower rates of NER and DSB/R (P < .0022), similar rates of ICL/R, and more condensed chromatin structure compared with nonresponders. Moreover, apoptosis rates of BMPCs were inversely correlated with individual DNA repair efficiency and were higher in responders{\textquoteright} cells compared with those of nonresponders (P = .0011). Similarly, RPMI8226 cells showed slower rates of NER and DSB/R, comparable rates of ICL/R, more condensed chromatin structure, and higher sensitivity than LR5 cells. Interestingly, cotreatment of BMPCs or cell lines with DSB/R inhibitors significantly reduced the rates ofDSB/R and increasedmelphalan sensitivity of the cells, with the nonhomologous end-joining inhibitor SCR7 showing the strongest effect. Together, responders{\textquoteright} BMPCs are characterized by lower efficiencies of NER and DSB/R mechanisms, resulting in higher accumulation of the extremely cytotoxic ICLs andDSBs lesions,which in turn triggers the induction of the apoptotic pathway. Moreover, the enhancement of melphalan cytotoxicity by DSB/R inhibition offers a promising strategy toward improvement of existing antimyeloma regimens. {\textcopyright} 2016 by The American Society of Hematology.},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84987600756\&doi=10.1182\%2fblood-2016-01-691618\&partnerID=40\&md5=02603e02b5e983e079d603b495133470},
	author = {Gkotzamanidou, M. and Terpos, E. and Bamia, C. and Munshi, N.C. and Dimopoulos, M.A. and Souliotis, V.L.}
}
