Systematic Phenotypic Screening for Novel Synergistic Combinations: A New Paradigm for Repositioning Existing Drugs

Drug Repositioning: Bringing New Life to Shelved Assets and Existing Drugs

Volumn , Issue , 2012, Pages 207-252

  Lee, Margaret S ^a  

^a Zalicus Inc   (United States)

Author keywords

Combination drug development, a single dose embodiment; Novel synergistic combinations, repurposed drug combinations; Systematic phenotypic screening, new paradigms in repositioning

Indexed keywords

EID: 84886488947     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9781118274408.ch8     Document Type: Chapter

References (110)

1. Gonzalez-Angulo, A.M., Hennessy, B.T., Mills, G.B. (2010). Future of personalized medicine in oncology: A systems biology approach. J. Clin. Oncol., 28, 2777-2783.
2. Lewanczuk, R., Tobe, S.W. (2007). More medications, fewer pills: Combination medications for the treatment of hypertension. Can. J. Cardiol., 23, 573-576.
3. Schiffman, D.O. (1975). Evaluation of an anti-infective combination. Trimethoprim - sulfamethoxazole (Bactrim, Septra). JAMA, 231, 635-637.
4. Feng, J.Y., Ly, J.K., Myrick, F., Goodman, D., White, K.L., Svarovskaia, E.S., Borroto-Esoda, K., Miller, M.D. (2009). The triple combination of tenofovir, emtricitabine and efavirenz shows synergistic anti-HIV-1 activity in vitro: A mechanism of action study. Retrovirology, 6, 44.
5. Hughes, B. (2009). Tapping into combination pills for HIV. Nat. Rev. Drug Discov., 8, 439-440.
6. Bliss, C. (1939). The toxicity of poisons applied jointly. Ann. Appl. Biol., 26, 585-615.
7. Berenbaum, M.C. (1989). What is synergy? Pharmacol. Rev., 41, 93-141.
8. Chou, T.C. (2006). Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol. Rev., 58, 621-681.
9. Greco, W.R., Bravo, G., Parsons, J.C. (1995). The search for synergy: A critical review from a response surface perspective. Pharmacol. Rev., 47, 331-385.
10. Loewe, S., Muischnek, H. (1926). Effect of combinations: Mathematical basis of the problem. Arch. Exp. Pathol. Pharmakol., 114, 313-326.
11. Lehar, J., Stockwell, B.R., Giaever, G., Nislow, C. (2008). Combination chemical genetics. Nat. Chem. Biol., 4, 674-681.
12. Chou, T.C., Talalay, P. (1984). Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul., 22, 27-55.
13. Lehar, J., Zimmermann, G.R., Krueger, A.S., Molnar, R.A., Ledell, J.T., Heilbut, A.M., Short, G.F., 3rd, Giusti, L.C., Nolan, G.P., Magid, O.A., Lee, M.S., Borisy, A.A., Stockwell, B.R., Keith, C.T. (2007). Chemical combination effects predict connectivity in biological systems. Mol. Syst. Biol., 3, 80.
14. Lehar, J., Krueger, A.S., Avery, W., Heilbut, A.M., Johansen, L.M., Price, E.R., Rickles, R.J., Short, G.F., 3rd, Staunton, J.E., Jin, X., Lee, M.S., Zimmermann, G.R., Borisy, A.A. (2009). Synergistic drug combinations tend to improve therapeutically relevant selectivity. Nat. Biotechnol., 27, 659-666.
15. Zimmermann, G.R., Lehar, J., Keith, C.T. (2007). Multi-target therapeutics: When the whole is greater than the sum of the parts. Drug Discov. Today, 12, 34-42.
16. Borisy, A.A., Elliott, P.J., Hurst, N.W., Lee, M.S., Lehar, J., Price, E.R., Serbedzija, G., Zimmermann, G.R., Foley, M.A., Stockwell, B.R., Keith, C.T. (2003). Systematic discovery of multicomponent therapeutics. Proc. Natl Acad. Sci. U.S.A., 100, 7977-7982.
17. Sharma, S.V., Haber, D.A., Settleman, J. (2010). Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents. Nat. Rev. Cancer, 10, 241-253.
18. Zimmermann, G.R., Avery, W., Finelli, A.L., Farwell, M., Fraser, C.C., Borisy, A.A. (2009). Selective amplification of glucocorticoid anti-inflammatory activity through synergistic multi-target action of a combination drug. Arthritis Res. Ther., 11, R12.
19. Hanahan, D., Weinberg, R.A. (2011). Hallmarks of cancer: The next generation. Cell, 144, 646-674.
20. Kim, S.H., Kuh, H.J., Dass, C.R. (2011). The reciprocal interaction: Chemotherapy and tumor microenvironment. Curr. Drug Discov. Technol., 8, 102-106.
21. Eberhard, Y., McDermott, S.P., Wang, X., Gronda, M., Venugopal, A., Wood, T.E., Hurren, R., Datti, A., Batey, R.A., Wrana, J., Antholine, W.E., Dick, J.E., Schimmer, A.D. (2009). Chelation of intracellular iron with the antifungal agent ciclopirox olamine induces cell death in leukemia and myeloma cells. Blood, 114, 3064-3073.
22. Sukhai, M.A., Spagnuolo, P.A., Weir, S., Kasper, J., Patton, L., Schimmer, A.D. (2011). New sources of drugs for hematologic malignancies. Blood, 117, 6747-6755.
23. Plane, J.M., Shen, Y., Pleasure, D.E., Deng, W. (2010). Prospects for minocycline neuroprotection. Arch. Neurol., 67, 1442-1448.
24. Black, C.B., Duensing, T.D., Trinkle, L.S., Dunlay, R.T. (2011). Cell-based screening using high-throughput flow cytometry. Assay Drug Dev. Technol., 9, 13-20.
25. Macarron, R., Banks, M.N., Bojanic, D., Burns, D.J., Cirovic, D.A., Garyantes, T., Green, D.V., Hertzberg, R.P., Janzen, W.P., Paslay, J.W., Schopfer, U., Sittampalam, G.S. (2011). Impact of high-throughput screening in biomedical research. Nat. Rev. Drug Discov., 10, 188-195.
26. Macarron, R., Hertzberg, R.P. (2011). Design and implementation of high throughput screening assays. Mol. Biotechnol., 47, 270-285.
27. Michelini, E., Cevenini, L., Mezzanotte, L., Coppa, A., Roda, A. (2010). Cell-based assays: Fuelling drug discovery. Anal. Bioanal. Chem., 398, 227-238.
28. Bickle, M. (2010). The beautiful cell: High-content screening in drug discovery. Anal. Bioanal. Chem., 398, 219-226.
29. Elliott, N.T., Yuan, F. (2010). A review of three-dimensional in vitro tissue models for drug discovery and transport studies. J. Pharm. Sci., 100, 59-74.
30. Ling, X.B. (2008). High throughput screening informatics. Comb. Chem. High Throughput Screen., 11, 249-257.
31. Schaeffer, S. (2011). For want of a nail, in BioCentury. A1-A5.
32. Schmitt, R., Traphagen, L., Hajduk, P. (2010). High throughput cherry-picking of solvated samples. Comb. Chem. High Throughput Screen., 13, 482-489.
33. Lehar, J., Krueger, A., Zimmermann, G., Borisy, A. (2008). High-order combination effects and biological robustness. Mol. Syst. Biol., 4, 215.
34. Heinemann, V. (2002). Gemcitabine plus cisplatin for the treatment of metastatic breast cancer. Clin. Breast Cancer, 3 (Suppl 1), 24-29.
35. Hanna, N.H., Einhorn, L.H. (2002). The value of platinum compounds in non - small-cell lung cancer. Clin. Lung Cancer, 3, 249-253.
36. Kroep, J.R., Pinedo, H.M., Giaccone, G., Van Bochove, A., Peters, G.J., Van Groeningen, C.J. (2004). Phase II study of cisplatin preceding gemcitabine in patients with advanced oesophageal cancer. Ann. Oncol., 15, 230-235.
37. Bergman, A.M., Ruiz Van Haperen, V.W., Veerman, G., Kuiper, C.M., Peters, G.J. (1996). Synergistic interaction between cisplatin and gemcitabine in vitro. Clin. Cancer Res., 2, 521-530.
38. van Moorsel, C.J., Kroep, J.R., Pinedo, H.M., Veerman, G., Voorn, D.A., Postmus, P.E., Vermorken, J.B., van Groeningen, C.J., van der Vijgh, W.J., Peters, G.J. (1999). Pharmacokinetic schedule finding study of the combination of gemcitabine and cisplatin in patients with solid tumors. Ann. Oncol., 10, 441-448.
39. Kroep, J.R., Peters, G.J., van Moorsel, C.J., Catik, A., Vermorken, J.B., Pinedo, H.M., van Groeningen, C.J. (1999). Gemcitabine-cisplatin: A schedule finding study. Ann. Oncol., 10, 1503-1510.
40. Loesch, D., Asmar, L., McIntyre, K., Doane, L., Monticelli, M., Paul, D., Vukelja, S., Orlando, M., Vaughn, L.G., Zhan, F., Boehm, K.A., O' Shaughnessy, J.A. (2008). Phase II trial of gemcitabine/carboplatin (plus trastuzumab in HER2 - positive disease) in patients with metastatic breast cancer. Clin. Breast Cancer, 8, 178-186.
41. Chew, H.K., Doroshow, J.H., Frankel, P., Margolin, K.A., Somlo, G., Lenz, H.J., Gordon, M., Zhang, W., Yang, D., Russell, C., Spicer, D., Synold, T., Bayer, R., Hantel, A., Stiff, P.J., Tetef, M.L., Gandara, D.R., Albain, K.S. (2009). Phase II studies of gemcitabine and cisplatin in heavily and minimally pretreated metastatic breast cancer. J. Clin. Oncol., 27, 2163-2169.
42. Shaffer, C. (2005). Automating compound management systems. Drug Discov. Devel., 8, 36-41.
43. Dragiev, P., Nadon, R., Makarenkov, V. (2011). Systematic error detection in experimental high-throughput screening. BMC Bioinformatics, 12, 25.
44. Makarenkov, V., Zentilli, P., Kevorkov, D., Gagarin, A., Malo, N., Nadon, R. (2007). An efficient method for the detection and elimination of systematic error in high - throughput screening. Bioinformatics, 23, 1648-1657.
45. Shun, T.Y., Lazo, J.S., Sharlow, E.R., Johnston, P.A. (2011). Identifying actives from HTS data sets: Practical approaches for the selection of an appropriate HTS data - processing method and quality control review. J. Biomol. Screen., 16, 1-14.
46. Cavalla, D. (2009). APT drug R & D: The right active ingredient in the right presentation for the right therapeutic use. Nat. Rev. Drug Discov., 8, 849-853.
47. Cavalla, D. (2005). Therapeutic switching: A new strategic approach to enhance R & D productivity. IDrugs, 8, 914-918.
48. Putcha, G.V., Johnson, E.M., Jr (2004). Men are but worms: Neuronal cell death in C elegans and vertebrates. Cell Death Differ., 11, 38-48.
49. St Johnston, D. (2002). The art and design of genetic screens: Drosophila melanogaster . Nat. Rev. Genet., 3, 176-188.
50. Pulverer, B. (2001). Trio united by division as cell cycle clinches centenary Nobel. Nature, 413, 553.
51. Speers, A.E., Adam, G.C., Cravatt, B.F. (2003). Activity-based protein profiling in vivo using a copper(i)-catalyzed azide-alkyne [3 + 2] cycloaddition. J. Am. Chem. Soc., 125, 4686-4687.
52. Speers, A.E., Cravatt, B.F. (2004). Profiling enzyme activities in vivo using click chemistry methods. Chem. Biol., 11, 535-546.
53. Speers, A.E., Cravatt, B.F. (2004). Chemical strategies for activity-based proteomics . Chembiochem, 5, 41-47.
54. Cardoso, I., Martins, D., Ribeiro, T., Merlini, G., Saraiva, M.J. (2010). Synergy of combined doxycycline/TUDCA treatment in lowering Transthyretin deposition and associated biomarkers: Studies in FAP mouse models. J. Transl. Med., 8, 74.
55. Cao, S., Durrani, F.A., Rustum, Y.M. (2005). Synergistic antitumor activity of capecitabine in combination with irinotecan. Clin. Colorectal Cancer, 4, 336-343.
56. Raftery, L., Goldberg, R.M. (2010). Optimal delivery of cytotoxic chemotherapy for colon cancer. Cancer J., 16, 214-219.
57. Renouf, D., Moore, M. (2010). Evolution of systemic therapy for advanced pancreatic cancer. Expert Rev. Anticancer Ther., 10, 529-540.
58. Hudis, C.A., Schmitz, N. (2004). Dose-dense chemotherapy in breast cancer and lymphoma. Semin. Oncol., 31, 19-26.
59. Lai, C.J., Bao, R., Tao, X., Wang, J., Atoyan, R., Qu, H., Wang, D.G., Yin, L., Samson, M., Forrester, J., Zifcak, B., Xu, G.X., DellaRocca, S., Zhai, H.X., Cai, X., Munger, W.E., Keegan, M., Pepicelli, C.V., Qian, C. (2010). CUDC-101, a multitargeted inhibitor of histone deacetylase, epidermal growth factor receptor, and human epidermal growth factor receptor 2, exerts potent anticancer activity. Cancer Res., 70, 3647-3656.
60. Cai, X., Zhai, H.X., Wang, J., Forrester, J., Qu, H., Yin, L., Lai, C.J., Bao, R., Qian, C. (2010). Discovery of 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin - 6-yloxy)-N-hydroxyheptanam ide (CUDc-101) as a potent multi-acting HDAC, EGFR, and HER2 inhibitor for the treatment of cancer. J. Med. Chem., 53, 2000-2009.
61. Mayer, L.D., Janoff, A.S. (2007). Optimizing combination chemotherapy by controlling drug ratios. Mol. Interv., 7, 216-223.
62. Mao, J., Gold, M.S., Backonja, M.M. (2011). Combination drug therapy for chronic pain: A call for more clinical studies. J. Pain, 12, 157-166.
63. Perez-Gracia, J.L., Berraondo, P., Martinez-Forero, I., Alfaro, C., Suarez, N., Gurpide, A., Sangro, B., Hervas-Stubbs, S., Ochoa, C., Melero, J.A., Melero, I. (2009). Clinical development of combination strategies in immunotherapy: Are we ready for more than one investigational product in an early clinical trial? Immunotherapy, 1, 845-853.
64. Srinivas, N.R. (2009). Is there a place for drug combination strategies using clinical pharmacology attributes? - Review of current trends in research. Curr. Clin. Pharmacol., 4, 220-228.
65. Barnett, A.H. (2009). Translating science into clinical practice: Focus on vildagliptin in combination with metformin. Diabetes Obes. Metab., 11 (Suppl 2), 18-26.
66. Ferrari, R. (2008). Optimizing the treatment of hypertension and stable coronary artery disease: Clinical evidence for fixed-combination perindopril/amlodipine. Curr. Med. Res. Opin., 24, 3543-3557.
67. Taylor, F., Smith, T. (2006). Use of combination therapy in migraine: A review of the clinical evidence. Postgrad. Med., Spec No, 27-31.
68. Donohue, J.F. (2005). Combination therapy for chronic obstructive pulmonary disease: Clinical aspects. Proc. Am. Thorac. Soc., 2, 272-281; discussion 290-271.
69. Baddley, J.W., Pappas, P.G. (2005). Antifungal combination therapy: Clinical potential. Drugs, 65, 1461-1480.
70. Division of Antiviral Drug Products in the Center for Drug Evaluation and Research (CDER) (2006). Fixed dose combinations, co-packaged drug products, and single-entity versions of previously approved antiretrovirals for the treatment of HIV, Food and Drug Administration.
71. Office of Medical Policy in the Center for Drug Evaluation and Research (CDER) (2010). Codevelopment of two or more unmarketed investigational drugs for use in combination, Food and Drug Administration.
72. Drug Information Branch, Division of Communications Management in the Center for Drug Evaluation and Research (CDER) (1999). Applications covered by section 505(b)(2). Food and Drug Administration.
73. U.S. Dept. of Heath and Human Services, Food and Drug Administration (31st, 2011). Approved Drug Produces with Therapeutic Equivalence Evaluations.
74. Deeks, E.D., Perry, C.M. (2010). Efavirenz/emtricitabine/tenofovir disoproxil fumarate single-tablet regimen (Atripla(R)): A review of its use in the management of HIV infection. Drugs, 70, 2315-2338.
75. Sanyal, S., Kuvin, J.T., Karas, R.H. (2010). Niacin and laropiprant. Drugs Today (Barc.), 46, 371-378.
76. Raffa, R.B., Pergolizzi, J.V., Jr (2010). Opioid formulations designed to resist/deter abuse. Drugs, 70, 1657-1675.
77. Ledermann, J.A., Gabra, H., Jayson, G.C., Spanswick, V.J., Rustin, G.J., Jitlal, M., James, L.E., Hartley, J.A. (2010). Inhibition of carboplatin-induced DNA interstrand cross-link repair by gemcitabine in patients receiving these drugs for platinum-resistant ovarian cancer. Clin. Cancer Res., 16, 4899-4905.
78. Crino, L., Scagliotti, G., Marangolo, M., Figoli, F., Clerici, M., De Marinis, F., Salvati, F., Cruciani, G., Dogliotti, L., Pucci, F., Paccagnella, A., Adamo, V., Altavilla, G., Incoronato, P., Trippetti, M., Mosconi, A.M., Santucci, A., Sorbolini, S., Oliva, C., Tonato, M. (1997). Cisplatin-gemcitabine combination in advanced non-small-cell lung cancer: A phase II study. J. Clin. Oncol., 15, 297-303.
79. Bertrand, M.E., Ferrari, R., Remme, W.J., Simoons, M.L., Deckers, J.W., Fox, K.M. (2010). Clinical synergy of perindopril and calcium-channel blocker in the prevention of cardiac events and mortality in patients with coronary artery disease. Post hoc analysis of the EUROPA study. Am. Heart J., 159, 795-802.
80. Jacobs, J.W., Bijlsma, J.W. (2009). Innovative combination strategy to enhance effect and diminish adverse effects of glucocorticoids: Another promise? Arthritis Res. Ther., 11, 105.
81. Kim, H.H., Liao, J.K. (2008). Translational therapeutics of dipyridamole. Arterioscler. Thromb. Vasc. Biol., 28, s39-s42.
82. Lowenberg, M., Stahn, C., Hommes, D.W., Buttgereit, F. (2008). Novel insights into mechanisms of glucocorticoid action and the development of new glucocorticoid receptor ligands. Steroids, 73, 1025-1029.
83. Cole, T.J. (2006). Glucocorticoid action and the development of selective glucocorticoid receptor ligands. Biotechnol. Annu. Rev., 12, 269-300.
84. Weyrich, A.S., Denis, M.M., Kuhlmann-Eyre, J.R., Spencer, E.D., Dixon, D.A., Marathe, G.K., McIntyre, T.M., Zimmerman, G.A., Prescott, S.M. (2005). Dipyridamole selectively inhibits inflammatory gene expression in platelet-monocyte aggregates. Circulation, 111, 633-642.
85. Fraser, C., Wang, Y., Finelli, A., Keith, C.T., Zimmermann, G. (2007). Inhibition of macrophage and chondrocyte inflammatory mediators by CRx-102, a novel synergistic combination drug candidate. EULAR Meet. Abstr., 66, 141.
86. Makowski, G.S., Ramsby, M.L. (2005). Autoactivation profiles of calcium - dependent matrix metalloproteinase-2 and-9 in inflammatory synovial fluid: Effect of pyrophosphate and bisphosphonates. Clin. Chim. Acta, 358, 182-191.
87. Yao, T.C., Kuo, M.L., See, L.C., Ou, L.S., Lee, W.I., Chan, C.K., Huang, J.L. (2006). RANTES and monocyte chemoattractant protein 1 as sensitive markers of disease activity in patients with juvenile rheumatoid arthritis: A six-year longitudinal study. Arthritis Rheum., 54, 2585-2593.
88. Stanczyk, J., Kowalski, M.L., Grzegorczyk, J., Szkudlinska, B., Jarzebska, M., Marciniak, M., Synder, M. (2005). RANTES and chemotactic activity in synovial fluids from patients with rheumatoid arthritis and osteoarthritis. Mediators Inflamm., 2005, 343-348.
89. Peake, N.J., Foster, H.E., Khawaja, K., Cawston, T.E., Rowan, A.D. (2006). Assessment of the clinical significance of gelatinase activity in patients with juvenile idiopathic arthritis using quantitative protein substrate zymography. Ann. Rheum. Dis., 65, 501-507.
90. Kirwan, J., George, E., Otsa, K., Clarke, S., Reid, D.M., Li, J., Lessem, J., Podrebarac, T.A. (2007). A phase 2a trial to evaluate CRx-102 for the treatment of active rheumatoid arthritis. EULAR Meet. Abstr., 66, 444.
91. Kvien, T.K., Fjeld, E., Slatkowsky-Christensen, B., Nichols, M., Zhang, Y., Proven, A., Mikkelsen, K., Palm, O., Borisy, A.A., Lessem, J. (2008). Efficacy and safety of a novel synergistic drug candidate, CRx-102, in hand osteoarthritis. Ann. Rheum. Dis., 67, 942-948.
92. Huttner, K., Shergy, W.J., Romney, C., Randle, J.C.R. (2009). CRx-102 (prednisolone/ dipyridamole combination) enhances glucocorticoid (GC) efficacy and reduces adverse effects in OA therapy: 3-12 month results. Arthritis Rheum., 60 (Suppl 10), 1943.
93. Richardson, P.G., Mitsiades, C., Schlossman, R., Munshi, N., Anderson, K. (2007). New drugs for myeloma. Oncologist, 12, 664-689.
94. Laubach, J., Richardson, P., Anderson, K. (2011). Multiple myeloma. Annu. Rev. Med., 62, 249-264.
95. Rickles, R.J., Pierce, L.T., Giordano, T.P., 3rd, Tam, W.F., McMillin, D.W., Delmore, J., Laubach, J.P., Borisy, A.A., Richardson, P.G., Lee, M.S. (2010). Adenosine A2A receptor agonists and PDE inhibitors: A synergistic multitarget mechanism discovered through systematic combination screening in B-cell malignancies. Blood, 116, 593-602.
96. Jacobson, K.A., Gao, Z.G. (2006). Adenosine receptors as therapeutic targets. Nat. Rev. Drug Discov., 5, 247-264.
97. Rickles, R.J., Pierce, L.T., Giordano, T.P., 3rd, Tam, W.F., Avery, W., Farwell, M., Crowe, D., Chen, M., Brown, A., Kansra, V., Nawrocki, S.T., Carew, J.S., Giles, F.J., Lee, M.S. (2008). Adenosine A2A and beta-2 adrenergic receptor agonism: Novel selective and synergistic multiple myeloma targets discovered through systematic combination screening. Blood, 112, Abstract 384.
98. Rickles, R.J., Tam, W.F., Necheva, A., Giordano, T.P., 3rd, Borisy, A., Lee, M.S. (2009). Adenosine A2A and beta-2 adrenergic receptor agonist synergy in B-cell malignancies: Selectivity, breadth of activity and effects of chronic exposure. Blood, 114, Abstract 3762.
99. McMillin, D.W., Rickles, R.J., Negri, J., Delmore, J., Ooi, M.G., Farwell, M., Crowe, D., Chen, M., Avery, W., Kansra, V., Anderson, K.C., Lee, M.S., Mitsiades, C. (2008). Synergistic activity of adenosine A2A and beta-2 adrenergic receptor agonists in myeloma cells in the context of tumor-stromal interactions. Blood, 112, Abstract 2663.
100. Rickles, R.J., Pierce, L.T., Giordano, T.P., 3rd, Avery, W., Farwell, M., Crowe, D., Tam, W.F., Chen, M., Kansra, V., McMillin, D.W., Anderson, K.C., Mitsiades, C., Lee, M.S. (2008). Preclinical evaluation of CRx-501, a potent selective A2A agonist as a novel drug candidate for the treatment of multiple myeloma. Blood, 112, Abstract 252.
101. Ballantyne, C.E. (2011). Clinical Data, I. Quarterly report for the period ending December 31, 2010.
102. Rickles, R.J., Padval, M., Giordano, T.P., 3rd, Rieger, J.M., Lee, M.S. (2010). ATL313, a potent and selective A2A agonist as a novel drug candidate for the treatment of multiple myeloma. Blood, 116, Abstract 2990.
103. Alam, M.S., Kurtz, C.C., Wilson, J.M., Burnette, B.R., Wiznerowicz, E.B., Ross, W.G., Rieger, J.M., Figler, R.A., Linden, J., Crowe, S.E., Ernst, P.B. (2009). A2A adenosine receptor (AR) activation inhibits pro-inflammatory cytokine production by human CD4 + helper T cells and regulates Helicobacter-induced gastritis and bacterial persistence. Mucosal Immunol., 2, 232-242.
104. Lappas, C.M., Rieger, J.M., Linden, J. (2005). A2A adenosine receptor induction inhibits IFN-gamma production in murine CD4 + T cells. J. Immunol., 174, 1073-1080.
105. Shaffer, A.L., Emre, N.C., Lamy, L., Ngo, V.N., Wright, G., Xiao, W., Powell, J., Dave, S., Yu, X., Zhao, H., Zeng, Y., Chen, B., Epstein, J., Staudt, L.M. (2008). IRF4 addiction in multiple myeloma. Nature, 454, 226-231.
106. Hurt, E.M., Wiestner, A., Rosenwald, A., Shaffer, A.L., Campo, E., Grogan, T., Bergsagel, P.L., Kuehl, W.M., Staudt, L.M. (2004). Overexpression of c-maf is a frequent oncogenic event in multiple myeloma that promotes proliferation and pathological interactions with bone marrow stroma. Cancer Cell, 5, 191-199.
107. Asano, J., Nakano, A., Oda, A., Amou, H., Hiasa, M., Takeuchi, K., Miki, H., Nakamura, S., Harada, T., Fujii, S., Kagawa, K., Endo, I., Yata, K., Sakai, A., Ozaki, S., Matsumoto, T., Abe, M. (2011). The serine/threonine kinase Pim-2 is a novel anti - apoptotic mediator in myeloma cells. Leukemia, 25, 1182-1188.
108. Ayroldi, E., Riccardi, C. (2009). Glucocorticoid-induced leucine zipper (GILZ): A new important mediator of glucocorticoid action. FASEB J., 23, 3649-3658.
109. Bartholow, M. (2011). Top 200 Drugs of 2010, in Pharmacy Times.
110. Kummar, S., Chen, H.X., Wright, J., Holbeck, S., Millin, M.D., Tomaszewski, J., Zweibel, J., Collins, J., Doroshow, J.H. (2010). Utilizing targeted cancer therapeutic agents in combination: Novel approaches and urgent requirements. Nat. Rev. Drug Discov., 9, 843-856.