The Impact of Molecularly Targeted Therapy in Multi-Modality Therapy

  • Shiyu Song
  • Paul Dent
  • Steven Grant
Part of the Medical Radiology book series (MEDRAD)


The development of a large number of targeted agents has introduced tremendous opportunities as well as challenges to the field of oncology. Although most agents show limited single drug potential for the cure of common solid neoplasms, they can prolong patient survival in selected tumor types and, most importantly, enhance the existing therapies for a variety of cancers. Improvements have been achieved in the treatment of hematological malignancies, colorectal cancer, renal cancer, lung cancer, head and neck cancer, breast cancer, and liver cancer. Because these agents do not cause side effects similar to those of cytotoxic drugs and radiation therapy, their combination with current conventional chemotherapy and radiotherapy is usually feasible. How to best combine these new agents with radiation and chemotherapy requires intensive and persistent efforts from both clinicians and research scientists.


Epidermal Growth Factor Receptor Clin Oncol Proteasome Inhibitor HDAC Inhibitor Acute Myelogenic Leukemia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Adams J (2004) The proteasome: a suitable antineoplastic target. Nat Rev Cancer 4:349−360PubMedGoogle Scholar
  2. Akinaga S, Sugiyama K, Akiyama T (2000) UCN-01 (7-hydroxystaurosporine) and other indolocarbazole compounds: A new generation of anti-cancer agents for the new century? Anticancer Drug Des 15:43−52PubMedGoogle Scholar
  3. Allan LA, Morrice N, Brady S et al. (2003) Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK. Nat Cell Biol 5:647−654PubMedGoogle Scholar
  4. Almenara J, Rosato R, Grant S (2002) Synergistic induction of mitochondrial damage and apoptosis in human leukemia cells by flavopiridol and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). Leukemia 16:1331−1343PubMedGoogle Scholar
  5. Almond JB, Cohen GM (2002) The proteasome: a novel target for cancer chemotherapy. Leukemia 16:433−443PubMedGoogle Scholar
  6. An B, Goldfarb RH, Siman R et al. (1998) Novel dipeptidyl proteasome inhibitors overcome Bcl-2 protective function and selectively accumulate the cyclin-dependent kinase inhibitor p27 and induce apoptosis in transformed, but not normal, human fibroblasts. Cell Death Differ 5:1062−1075PubMedGoogle Scholar
  7. Arguello F, Alexander M, Sterry JA et al. (1998) Flavopiridol induces apoptosis of normal lymphoid cells, causes immunosuppression, and has potent antitumor activity in vivo against human leukemia and lymphoma xenografts. Blood 91:2482−2490PubMedGoogle Scholar
  8. Arora A, Scholar EM (2005) Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther 315:971−979PubMedGoogle Scholar
  9. Astsaturov I, Cohen RB, Harari P (2006) Targeting epidermal growth factor receptor signaling in the treatment of head and neck cancer. Expert Rev Anticancer Ther 6:1179−1193PubMedGoogle Scholar
  10. Balaban N, Moni J, Shannon M et al. (1996) The effect of ionizing radiation on signal transduction: antibodies to EGF receptor sensitize A431 cells to radiation. Biochim Biophys Acta 1314:147−156PubMedGoogle Scholar
  11. Bali P, Pranpat M, Bradner J et al. (2005) Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J Biol Chem 280:26729−26734PubMedGoogle Scholar
  12. Baselga J, Arteaga CL (2005) Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol 23:2445−2459PubMedGoogle Scholar
  13. Baumann M, Krause M, Dikomey E et al. (2007) EGFR-targeted anti-cancer drugs in radiotherapy: preclinical evaluation of mechanisms. Radiother Oncol 83:238−248PubMedGoogle Scholar
  14. Bentzen SM, Atasoy BM, Daley FM et al. (2005) Epidermal growth factor receptor expression in pretreatment biopsies from head and neck squamous cell carcinoma as a predictive factor for a benefit from accelerated radiation therapy in a randomized controlled trial. J Clin Oncol 23:5560−5567PubMedGoogle Scholar
  15. Bianco C, Tortora G, Bianco R et al. (2002) Enhancement of antitumor activity of ionizing radiation by combined treatment with the selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 (Iressa). Clin Cancer Res 8:3250−3258PubMedGoogle Scholar
  16. Blanke CD, Rankin C, Demetri GD et al. (2008) Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 26:626−632PubMedGoogle Scholar
  17. Bonner JA, Harari PM, Giralt J et al. (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567−578PubMedGoogle Scholar
  18. Bowers G, Reardon D, Hewitt T et al. (2001) The relative role of ErbB1-4 receptor tyrosine kinases in radiation signal transduction responses of human carcinoma cells. Oncogene 20:1388−1397PubMedGoogle Scholar
  19. Bunch RT, Eastman A (1996) Enhancement of cisplatin-induced cytotoxicity by 7-hydroxystaurosporine (UCN-01), a new G2-checkpoint inhibitor. Clin Cancer Res 2:791−797PubMedGoogle Scholar
  20. Caro AA, Cederbaum AI (2006) Role of phosphatidylinositol 3-kinase/AKT as a survival pathway against CYP2E1-dependent toxicity. J Pharmacol Exp Ther 318:360−372PubMedGoogle Scholar
  21. Caron RW, Yacoub A, Li M et al. (2005) Activated forms of H-RAS and K-RAS differentially regulate membrane association of PI3K, PDK-1, and AKT and the effect of therapeutic kinase inhibitors on cell survival. Mol Cancer Ther 4:257−270PubMedGoogle Scholar
  22. Cartee L, Sankala H, Davis C et al. (2002) 7-hydroxystaurosporine (UCN-01) and ionizing radiation combine to inhibit the growth of Bcl-2-overexpressing U937 leukemia cells through a non-apoptotic mechanism. Int J Oncol 21:351−359PubMedGoogle Scholar
  23. Champagne MA, Capdeville R, Krailo M et al. (2004) Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosome-positive leukemia: results from a Children’s Oncology Group phase 1 study. Blood 104:2655−2660PubMedGoogle Scholar
  24. Chao SH, Price DH (2001) Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo. J Biol Chem 276:31793−31799PubMedGoogle Scholar
  25. Chen LF, Greene WC (2003) Regulation of distinct biological activities of the NF-kappaB transcription factor complex by acetylation. J Mol Med 81:549−557PubMedGoogle Scholar
  26. Chen LF, Greene WC (2004) Shaping the nuclear action of NF-kappaB. Nat Rev Mol Cell Biol 5:392−401PubMedGoogle Scholar
  27. Chinnaiyan P, Huang S, Vallabhaneni G et al. (2005) Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva). Cancer Res 65:3328−3335PubMedGoogle Scholar
  28. Chinnaiyan P, Allen GW, Harari PM (2006) Radiation and new molecular agents, part II: targeting HDAC, HSP90, IGF-1R, PI3K, and Ras. Semin Radiat Oncol 16:59−64PubMedGoogle Scholar
  29. Choe MS, Chen Z, Klass CM et al. (2007) Enhancement of docetaxel-induced cytotoxicity by blocking epidermal growth factor receptor and cyclooxygenase-2 pathways in squamous cell carcinoma of the head and neck. Clin Cancer Res 13:3015−3023PubMedGoogle Scholar
  30. Chu S, Holtz M, Gupta M et al. (2004) BCR/ABL kinase inhibition by imatinib mesylate enhances MAP kinase activity in chronic myelogenous leukemia CD34+ cells. Blood 103:3167−3174PubMedGoogle Scholar
  31. Ciechanover A (2005) Intracellular protein degradation: from a vague idea, through the lysosome and the ubiquitin-proteasome system, and onto human diseases and drug targeting (Nobel lecture). Angew Chem Int Ed Engl 44:5944−5967PubMedGoogle Scholar
  32. Cohen MH, Williams GA, Sridhara R et al. (2004) United States Food and Drug Administration Drug Approval summary:Gefitinib (ZD1839; Iressa) tablets. Clin Cancer Res 10:1212−1218PubMedGoogle Scholar
  33. Cortes J, Rousselot P, Kim DW et al. (2007) Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 109:3207−3213PubMedGoogle Scholar
  34. Cunningham D, Humblet Y, Siena S et al. (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337−345PubMedGoogle Scholar
  35. Dai Y, Yu C, Singh V et al. (2001) Pharmacological inhibitors of the mitogen-activated protein kinase (MAPK) kinase/MAPK cascade interact synergistically with UCN-01 to induce mitochondrial dysfunction and apoptosis in human leukemia cells. Cancer Res 61:5106−5115PubMedGoogle Scholar
  36. Dai Y, Landowski TH, Rosen ST et al. (2002) Combined treatment with the checkpoint abrogator UCN-01 and MEK1/2 inhibitors potently induces apoptosis in drug-sensitive and -resistant myeloma cells through an IL-6-independent mechanism. Blood 100:3333−3343PubMedGoogle Scholar
  37. Dai Y, Rahmani M, Grant S (2003a) An intact NF-kappaB pathway is required for histone deacetylase inhibitor-induced G1 arrest and maturation in U937 human myeloid leukemia cells. Cell Cycle 2:467−472Google Scholar
  38. Dai Y, Rahmani M,Grant S (2003b) Proteasome inhibitors potentiate leukemic cell apoptosis induced by the cyclin-dependent kinase inhibitor flavopiridol through a SAPK/JNK- and NF-kappaB-dependent process. Oncogene 22:7108−7122Google Scholar
  39. Dai Y, Dent P, Grant S (2003c) Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) promotes mitochondrial dysfunction and apoptosis induced by 7-hydroxystaurosporine and mitogen-activated protein kinase kinase inhibitors in human leukemia cells that ectopically express Bcl-2 and Bcl-xL. Mol Pharmacol 64:1402−1409Google Scholar
  40. Dai Y, Rahmani M, Pei XY et al. (2004a) Bortezomib and flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms. Blood 104:509−518Google Scholar
  41. Dai Y, Pei XY, Rahmani M et al. (2004b) Interruption of the NF-kappaB pathway by Bay 11-7082 promotes UCN-01-mediated mitochondrial dysfunction and apoptosis in human multiple myeloma cells. Blood 103:2761−2770Google Scholar
  42. Dai Y, Rahmani M, Pei XY et al. (2005a) Farnesyltransferase inhibitors interact synergistically with the Chk1 inhibitor UCN-01 to induce apoptosis in human leukemia cells through interruption of both Akt and MEK/ERK pathways and activation of SEK1/JNK. Blood 105:1706−1716Google Scholar
  43. Dai Y, Rahmani M, Dent P et al. (2005b) Blockade of histone deacetylase inhibitor-induced RelA/p65 acetylation and NF-kappaB activation potentiates apoptosis in leukemia cells through a process mediated by oxidative damage, XIAP downregulation, and c-Jun N-terminal kinase 1 activation. Mol Cell Biol 25:5429−5444Google Scholar
  44. Dai Y, Chen S, Venditti CA et al. (2008) Vorinostat synergistically potentiates MK-0457 lethality in chronic myelogenous leukemia cells sensitive and resistant to imatinib mesylate. Blood 112:793−804PubMedGoogle Scholar
  45. Dancey JE, Chen HX (2006) Strategies for optimizing combinations of molecularly targeted anticancer agents. Nat Rev Drug Discov 5:649−659PubMedGoogle Scholar
  46. Dassonville O, Bozec A, Fischel JL et al. (2007) EGFR targeting therapies: monoclonal antibodies versus tyrosine kinase inhibitors. Similarities and differences. Crit Rev Oncol Hematol 62:53−61PubMedGoogle Scholar
  47. Datta SR, Brunet A, Greenberg ME (1999) Cellular survival: a play in three Akts. Genes Dev 13:2905−2927PubMedGoogle Scholar
  48. Dent P, Reardon DB, Park JS et al. (1999) Radiation-induced release of transforming growth factor alpha activates the epidermal growth factor receptor and mitogen-activated protein kinase pathway in carcinoma cells, leading to increased proliferation and protection from radiation-induced cell death. Mol Biol Cell 10:2493−2506PubMedGoogle Scholar
  49. Druker BJ, Guilhot F, O’Brien SG et al. (2006) Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355:2408−2417PubMedGoogle Scholar
  50. Escudier B, Eisen T, Stadler WM et al. (2007a) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125−134Google Scholar
  51. Escudier B, Pluzanska A, Koralewski P et al. (2007b) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370:2103−2111Google Scholar
  52. Fang L, Li G, Liu G et al. (2001) p53 induction of heparin-binding EGF-like growth factor counteracts p53 growth suppression through activation of MAPK and PI3K/Akt signaling cascades. Embo J 20:1931−1939PubMedGoogle Scholar
  53. Fleming IN, Hogben M, Frame S et al. (2008) Synergistic inhibition of ErbB signaling by combined treatment with seliciclib and ErbB-targeting agents. Clin Cancer Res 14:4326−4335PubMedGoogle Scholar
  54. Fukuoka M, Yano S, Giaccone G et al. (2003) Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol 21:2237−2246PubMedGoogle Scholar
  55. Furukawa Y, Vu HA, Akutsu M et al. (2007) Divergent cytotoxic effects of PKC412 in combination with conventional antileukemic agents in FLT3 mutation-positive versus -negative leukemia cell lines. Leukemia 21:1005−1014PubMedGoogle Scholar
  56. Gao N, Dai Y, Rahmani M et al. (2004) Contribution of disruption of the nuclear factor-kappaB pathway to induction of apoptosis in human leukemia cells by histone deacetylase inhibitors and flavopiridol. Mol Pharmacol 66:956−963PubMedGoogle Scholar
  57. Gao N, Rahmani M, Shi X et al. (2006) Synergistic antileukemic interactions between 2-medroxyestradiol (2-ME) and histone deacetylase inhibitors involve Akt down-regulation and oxidative stress. Blood 107:241−249PubMedGoogle Scholar
  58. Garcia-Manero G, Issa JP (2005) Histone deacetylase inhibitors: a review of their clinical status as antineoplastic agents. Cancer Invest 23:635−642PubMedGoogle Scholar
  59. Gatzemeier U, Pluzanska A, Szczesna A et al. (2007) Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol 25:1545−1552PubMedGoogle Scholar
  60. George P, Bali P, Annavarapu S et al. (2005) Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. Blood 105:1768−1776PubMedGoogle Scholar
  61. Gerber DE (2008) Targeted therapies: a new generation of cancer treatments. Am Fam Physician 77:311−319PubMedGoogle Scholar
  62. Geyer CE, Forster J, Lindquist D et al. (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733−2743PubMedGoogle Scholar
  63. Giaccone G, Herbst RS, Manegold C et al. (2004) Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial − INTACT 1. J Clin Oncol 22:777−784PubMedGoogle Scholar
  64. Giantonio BJ, Catalano PJ, Meropol NJ et al. (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25:1539−1544PubMedGoogle Scholar
  65. Gise A von, Lorenz P, Wellbrock C et al. (2001) Apoptosis suppression by Raf-1 and MEK1 requires MEK- and phosphatidylinositol 3-kinase-dependent signals. Mol Cell Biol 21:2324−2336Google Scholar
  66. Giuliano M, Lauricella M, Calvaruso G et al. (1999) The apoptotic effects and synergistic interaction of sodium butyrate and MG132 in human retinoblastoma Y79 cells. Cancer Res 59:5586−5595PubMedGoogle Scholar
  67. Gorre ME, Ellwood-Yen K, Chiosis G et al. (2002) BCR-ABL point mutants isolated from patients with imatinib mesylate-resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90. Blood 100:3041−3044PubMedGoogle Scholar
  68. Gottlieb E, Vander Heiden MG, Thompson CB (2000) Bcl-x(L) prevents the initial decrease in mitochondrial membrane potential and subsequent reactive oxygen species production during tumor necrosis factor alpha-induced apoptosis. Mol Cell Biol 20:5680−5689PubMedGoogle Scholar
  69. Graves PR, Yu L, Schwarz JK et al. (2000) The Chk1 protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01. J Biol Chem 275:5600−5605PubMedGoogle Scholar
  70. Grethe S, Porn-Ares MI (2006) p38 MAPK regulates phosphorylation of Bad via PP2A-dependent suppression of the MEK1/2-ERK1/2 survival pathway in TNF-alpha induced endothelial apoptosis. Cell Signal 18:531−540PubMedGoogle Scholar
  71. Guilhot F, Apperley J, Kim DW et al. (2007) Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 109:4143−4150PubMedGoogle Scholar
  72. Guo F, Sigua C, Tao J et al. (2004) 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 Res 64:2580−2589PubMedGoogle Scholar
  73. Gupta AK, Bernhard EJ, Bakanauskas VJ et al. (2000) RAS-Mediated radiation resistance is not linked to MAP kinase activation in two bladder carcinoma cell lines. Radiat Res 154:64−72PubMedGoogle Scholar
  74. Gupta AK, Bakanauskas VJ, Cerniglia GJ et al. (2001) The Ras radiation resistance pathway. Cancer Res 61:4278−4282PubMedGoogle Scholar
  75. Hagan M, Yacoub A, Dent P (2004) Ionizing radiation causes a dose-dependent release of transforming growth factor alpha in vitro from irradiated xenografts and during palliative treatment of hormone-refractory prostate carcinoma. Clin Cancer Res 10:5724−5731PubMedGoogle Scholar
  76. Hahn M, Li W, Yu C et al. (2005) Rapamycin and UCN-01 synergistically induce apoptosis in human leukemia cells through a process that is regulated by the Raf-1/MEK/ERK, Akt, and JNK signal transduction pathways. Mol Cancer Ther 4:457−470PubMedGoogle Scholar
  77. Han JW, Ahn SH, Park SH et al. (2000) Apicidin, a histone deacetylase inhibitor, inhibits proliferation of tumor cells via induction of p21WAF1/Cip1 and gelsolin. Cancer Res 60:6068−6074PubMedGoogle Scholar
  78. Harari PM (2007) Stepwise progress in epidermal growth factor receptor/radiation studies for head and neck cancer. Int J Radiat Oncol Biol Phys 69:S25−S27PubMedGoogle Scholar
  79. Harari PM, Huang S (2006) Radiation combined with EGFR signal inhibitors: head and neck cancer focus. Semin Radiat Oncol 16:38−44PubMedGoogle Scholar
  80. Heinrich MC, Corless CL, Demetri GD et al. (2003) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342−4349PubMedGoogle Scholar
  81. Herbst RS, Giaccone G, Schiller JH et al. (2004) Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial: INTACT 2. J Clin Oncol 22:785−794PubMedGoogle Scholar
  82. Herbst RS, Prager D, Hermann R et al. (2005) TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 23:5892−5899PubMedGoogle Scholar
  83. Hochhaus A, Kantarjian HM, Baccarani M et al. (2007) Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 109:2303−2309PubMedGoogle Scholar
  84. Hostein I, Robertson D, DiStefano F et al. (2001) Inhibition of signal transduction by the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin results in cytostasis and apoptosis. Cancer Res 61:4003−4009PubMedGoogle Scholar
  85. Huang SM, Harari PM (2000) Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis. Clin Cancer Res 6:2166−2174PubMedGoogle Scholar
  86. Huang P, Feng L, Oldham EA et al. (2000) Superoxide dismutase as a target for the selective killing of cancer cells. Nature 407:390−395PubMedGoogle Scholar
  87. Hudes G, Carducci M, Tomczak P et al. (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356:2271−2281PubMedGoogle Scholar
  88. Hurwitz H, Fehrenbacher L, Novotny W et al. (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335−2342PubMedGoogle Scholar
  89. Hutcheson IR, Knowlden JM, Jones HE et al. (2006) Inductive mechanisms limiting response to anti-epidermal growth factor receptor therapy. Endocr Relat Cancer 13 (Suppl 1):S89−S97PubMedGoogle Scholar
  90. Ihle NT, Paine-Murrieta G, Berggren MI et al. (2005) The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non-small cell lung cancer xenografts. Mol Cancer Ther 4:1349−1357PubMedGoogle Scholar
  91. Insinga A, Monestiroli S, Ronzoni S et al. (2005) Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway. Nat Med 11:71−76PubMedGoogle Scholar
  92. Jia W, Yu C, Rahmani M et al. (2003) Synergistic antileukemic interactions between 17-AAG and UCN-01 involve interruption of RAF/MEK- and AKT-related pathways. Blood 102:1824−1832PubMedGoogle Scholar
  93. Jonker DJ, O’Callaghan CJ, Karapetis CS et al. (2007) Cetuximab for the treatment of colorectal cancer. N Engl J Med 357:2040−2048PubMedGoogle Scholar
  94. Kabbinavar FF, Schulz J, McCleod M et al. (2005) Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 23:3697−3705PubMedGoogle Scholar
  95. Kastan MB (2001) Cell cycle. Checking two steps. Nature 410:766−767PubMedGoogle Scholar
  96. Kastan MB, Bartek J (2004) Cell-cycle checkpoints and cancer. Nature 432:316−323PubMedGoogle Scholar
  97. Kavanagh BD, Lin PS, Chen P et al. (1995) Radiation-induced enhanced proliferation of human squamous cancer cells in vitro: a release from inhibition by epidermal growth factor. Clin Cancer Res 1:1557−1562PubMedGoogle Scholar
  98. Kim DW, Huamani J, Fu A et al. (2006) Molecular strategies targeting the host component of cancer to enhance tumor response to radiation therapy. Int J Radiat Oncol Biol Phys 64:38−46PubMedGoogle Scholar
  99. Kondapaka SB, Singh SS, Dasmahapatra GP et al. (2003) Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. Mol Cancer Ther 2:1093−1103PubMedGoogle Scholar
  100. Krieg M, Haas R, Brauch H et al. (2000) Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function. Oncogene 19:5435−5443PubMedGoogle Scholar
  101. Kris MG, Natale RB, Herbst RS et al. (2003) Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. J Am Med Assoc 290:2149−2158Google Scholar
  102. Kwak EL, Sordella R, Bell DW et al. (2005) Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci U S A 102:7665−7670PubMedGoogle Scholar
  103. Langer CJ (2004) Emerging role of epidermal growth factor receptor inhibition in therapy for advanced malignancy: focus on NSCLC. Int J Radiat Oncol Biol Phys 58:991−1002PubMedGoogle Scholar
  104. Lee BH, Williams IR, Anastasiadou E et al. (2005) FLT3 internal tandem duplication mutations induce myeloproliferative or lymphoid disease in a transgenic mouse model. Oncogene 24:7882−7892PubMedGoogle Scholar
  105. Li H, Zhu H, Xu CJ et al. (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94:491−501PubMedGoogle Scholar
  106. Ling YH, Liebes L, Zou Y et al. (2003) Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic response to Bortezomib, a novel proteasome inhibitor, in human H460 non-small cell lung cancer cells. J Biol Chem 278:33714−33723PubMedGoogle Scholar
  107. Llovet JM, Ricci S, Mazzaferro V et al. (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378−390PubMedGoogle Scholar
  108. Lynch TJ, Bell DW, Sordella R et al. (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129−2139PubMedGoogle Scholar
  109. Majumdar AP, Du J (2006) Phosphatidylinositol 3-kinase/Akt signaling stimulates colonic mucosal cell survival during aging. Am J Physiol Gastrointest Liver Physiol 290:G49−G55PubMedGoogle Scholar
  110. Marcucci G, Byrd JC, Dai G et al. (2003) Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia. Blood 101:425−432PubMedGoogle Scholar
  111. Marks PA, Jiang X (2005) Histone deacetylase inhibitors in programmed cell death and cancer therapy. Cell Cycle 4:549−551PubMedGoogle Scholar
  112. Marks PA, Miller T, Richon VM (2003) Histone deacetylases. Curr Opin Pharmacol 3:344−351PubMedGoogle Scholar
  113. McKinstry R, Qiao L, Yacoub A et al. (2002) Inhibitors of MEK1/2 interact with UCN-01 to induce apoptosis and reduce colony formation in mammary and prostate carcinoma cells. Cancer Biol Ther 1:243−253PubMedGoogle Scholar
  114. Milella M, Kornblau SM, Estrov Z et al. (2001) Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia. J Clin Invest 108:851−859PubMedGoogle Scholar
  115. Miller K, Wang M, Gralow J et al. (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666−2676PubMedGoogle Scholar
  116. Molhoek KR, Brautigan DL, Slingluff CL Jr (2005) Synergistic inhibition of human melanoma proliferation by combination treatment with B-Raf inhibitor BAY43-9006 and mTOR inhibitor Rapamycin. J Transl Med 3:39PubMedGoogle Scholar
  117. Momparler RL (2005) Epigenetic therapy of cancer with 5-aza-2'-deoxycytidine (decitabine). Semin Oncol 32:443−451PubMedGoogle Scholar
  118. Motzer RJ, Hutson TE, Tomczak P et al. (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115−124PubMedGoogle Scholar
  119. Muller CI, Ruter B, Koeffler HP et al. (2006) DNA hypermethylation of myeloid cells, a novel therapeutic target in MDS and AML. Curr Pharm Biotechnol 7:315−321PubMedGoogle Scholar
  120. Murdoch D, Sager J (2008) Will targeted therapy hold its promise? An evidence-based review. Curr Opin Oncol 20:104−111PubMedGoogle Scholar
  121. Na X, Wu G, Ryan CK et al. (2003) Overproduction of vascular endothelial growth factor related to von Hippel-Lindau tumor suppressor gene mutations and hypoxia-inducible factor-1 alpha expression in renal cell carcinomas. J Urol 170:588−592PubMedGoogle Scholar
  122. Neckers L, Ivy SP (2003) Heat shock protein 90. Curr Opin Oncol 15:419−424PubMedGoogle Scholar
  123. Nishi H, Senoo M, Nishi KH et al. (2001) p53 Homologue p63 represses epidermal growth factor receptor expression. J Biol Chem 276:41717−41724PubMedGoogle Scholar
  124. Nowell PC, Hungerford DA (1961) Chromosome studies in human leukemia. II. Chronic granulocytic leukemia. J Natl Cancer Inst 27:1013−1035PubMedGoogle Scholar
  125. O’Connor OA, Wright J, Moskowitz C et al. (2005) Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin’s lymphoma and mantle cell lymphoma. J Clin Oncol 23:676−684PubMedGoogle Scholar
  126. Oltersdorf T, Elmore SW, Shoemaker AR et al. (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435:677−681PubMedGoogle Scholar
  127. Orlowski RZ, Small GW,Shi YY (2002) Evidence that inhibition of p44/42 mitogen-activated protein kinase signaling is a factor in proteasome inhibitor-mediated apoptosis. J Biol Chem 277:27864−27871PubMedGoogle Scholar
  128. Osaki M, Kase S, Adachi K et al. (2004) Inhibition of the PI3K-Akt signaling pathway enhances the sensitivity of Fas-mediated apoptosis in human gastric carcinoma cell line, MKN-45. J Cancer Res Clin Oncol 130:8−14PubMedGoogle Scholar
  129. Pan G, Ni J, Wei YF et al. (1997) An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science 277:815−818PubMedGoogle Scholar
  130. Pei XY, Dai Y, Grant S (2003) The proteasome inhibitor bortezomib promotes mitochondrial injury and apoptosis induced by the small molecule Bcl-2 inhibitor HA14-1 in multiple myeloma cells. Leukemia 17:2036−2045PubMedGoogle Scholar
  131. Pei XY, Dai Y, Grant S (2004a) Synergistic induction of oxidative injury and apoptosis in human multiple myeloma cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitors. Clin Cancer Res 10:3839−3852Google Scholar
  132. Pei XY, Dai Y,Grant S (2004b) The small-molecule Bcl-2 inhibitor HA14-1 interacts synergistically with flavopiridol to induce mitochondrial injury and apoptosis in human myeloma cells through a free radical-dependent and Jun NH2-terminal kinase-dependent mechanism. Mol Cancer Ther 3:1513−1524Google Scholar
  133. Peterson CL, Laniel MA (2004) Histones and histone modifications. Curr Biol 14:R546−R551PubMedGoogle Scholar
  134. Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al. (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659−1672PubMedGoogle Scholar
  135. Rahmani M, Yu C, Reese E et al. (2003a) Inhibition of PI-3 kinase sensitizes human leukemic cells to histone deacetylase inhibitor-mediated apoptosis through p44/42 MAP kinase inactivation and abrogation of p21(CIP1/WAF1) induction rather than AKT inhibition. Oncogene 22:6231−6242Google Scholar
  136. Rahmani M, Yu C, Dai Y et al. (2003b) Coadministration of the heat shock protein 90 antagonist 17-allylamino- 17-demethoxygeldanamycin with suberoylanilide hydroxamic acid or sodium butyrate synergistically induces apoptosis in human leukemia cells. Cancer Res 63:8420−8427Google Scholar
  137. Ratain MJ, Eisen T, Stadler WM et al. (2006) Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 24:2505−2512PubMedGoogle Scholar
  138. Ray A, Cowan-Jacob SW, Manley PW et al. (2007) Identification of BCR-ABL point mutations conferring resistance to the Abl kinase inhibitor AMN107 (nilotinib) by a random mutagenesis study. Blood 109:5011−5015PubMedGoogle Scholar
  139. Reed JC (1998) Bcl-2 family proteins. Oncogene 17:3225−3236PubMedGoogle Scholar
  140. Rinehart J, Adjei AA, Lorusso PM et al. (2004) Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J Clin Oncol 22:4456−4462PubMedGoogle Scholar
  141. Romond EH, Perez EA, Bryant J et al. (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673−1684PubMedGoogle Scholar
  142. Rosato RR, Grant S (2003) Histone deacetylase inhibitors in cancer therapy. Cancer Biol Ther 2:30−37PubMedGoogle Scholar
  143. Rosato RR, Wang Z, Gopalkrishnan RV et al. (2001) Evidence of a functional role for the cyclin-dependent kinase-inhibitor p21WAF1/CIP1/MDA6 in promoting differentiation and preventing mitochondrial dysfunction and apoptosis induced by sodium butyrate in human myelomonocytic leukemia cells (U937). Int J Oncol 19:181−191PubMedGoogle Scholar
  144. Rosato RR, Almenara JA, Dai Y et al. (2003) Simultaneous activation of the intrinsic and extrinsic pathways by histone deacetylase (HDAC) inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) synergistically induces mitochondrial damage and apoptosis in human leukemia cells. Mol Cancer Ther 2:1273−1284PubMedGoogle Scholar
  145. Rosato RR, Dai Y, Almenara JA et al. (2004) Potent antileukemic interactions between flavopiridol and TRAIL/Apo2L involve flavopiridol-mediated XIAP downregulation. Leukemia 18:1780−1788PubMedGoogle Scholar
  146. Ruefli AA, Ausserlechner MJ, Bernhard D et al. (2001) The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of Bid and production of reactive oxygen species. Proc Natl Acad Sci U S A 98:10833−10838PubMedGoogle Scholar
  147. Saltz LB, Meropol NJ, Loehrer PJ Sr et al. (2004) Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22:1201−1208PubMedGoogle Scholar
  148. Sandler A, Herbst R (2006) Combining targeted agents: blocking the epidermal growth factor and vascular endothelial growth factor pathways. Clin Cancer Res 12:4421s−4425sPubMedGoogle Scholar
  149. Sandler A, Gray R, Perry MC et al. (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542−2550PubMedGoogle Scholar
  150. Santoro A, Cavina R, Latteri F et al. (2004) Activity of a specific inhibitor, gefitinib (Iressa, ZD1839), of epidermal growth factor receptor in refractory non-small-cell lung cancer. Ann Oncol 15:33−37PubMedGoogle Scholar
  151. Sato S, Fujita N,Tsuruo T (2002) Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine). Oncogene 21:1727−1738PubMedGoogle Scholar
  152. Sawyers CL, Hochhaus A, Feldman E et al. (2002) Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 99:3530−3539PubMedGoogle Scholar
  153. Schimmer AD, Welsh K, Pinilla C et al. (2004) Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity. Cancer Cell 5:25−35PubMedGoogle Scholar
  154. Schmidt-Ullrich RK, Valerie K, Chan W et al. (1992) Expression of oestrogen receptor and transforming growth factor-alpha in MCF-7 cells after exposure to fractionated irradiation. Int J Radiat Biol 61:405−415PubMedGoogle Scholar
  155. Senderowicz AM (1999) Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials. Invest New Drugs 17:313−320PubMedGoogle Scholar
  156. Sengupta N, Seto E (2004) Regulation of histone deacetylase activities. J Cell Biochem 93:57−67PubMedGoogle Scholar
  157. Shao RG, Cao CX, Shimizu T et al. (1997) Abrogation of an S-phase checkpoint and potentiation of camptothecin cytotoxicity by 7-hydroxystaurosporine (UCN-01) in human cancer cell lines, possibly influenced by p53 function. Cancer Res 57:4029−4035PubMedGoogle Scholar
  158. Sheikh MS, Carrier F, Johnson AC et al. (1997) Identification of an additional p53-responsive site in the human epidermal growth factor receptor gene promotor. Oncogene 15:1095−1101PubMedGoogle Scholar
  159. Shelton JG, Steelman LS, Abrams SL et al. (2005) The epidermal growth factor receptor gene family as a target for therapeutic intervention in numerous cancers: What’s genetics got to do with it? Expert Opin Ther Targets 9:1009−1030PubMedGoogle Scholar
  160. Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al. (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123−132PubMedGoogle Scholar
  161. Sheridan JP, Marsters SA, Pitti RM et al. (1997) Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 277:818−821PubMedGoogle Scholar
  162. Shibuya K, Komaki R, Shintani T et al. (2007) Targeted therapy against VEGFR and EGFR with ZD6474 enhances the therapeutic efficacy of irradiation in an orthotopic model of human non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 69:1534−1543PubMedGoogle Scholar
  163. Shonai T, Adachi M, Sakata K et al. (2002) MEK/ERK pathway protects ionizing radiation-induced loss of mitochondrial membrane potential and cell death in lymphocytic leukemia cells. Cell Death Differ 9:963−971PubMedGoogle Scholar
  164. Shvartsman SY, Hagan MP, Yacoub A et al. (2002) Autocrine loops with positive feedback enable context-dependent cell signaling. Am J Physiol Cell Physiol 282:C545−C559PubMedGoogle Scholar
  165. Simon GR, Ruckdeschel JC, Williams C et al. (2003) Gefitinib (ZD1839) in previously treated advanced non-small-cell lung cancer: experience from a single institution. Cancer Control 10:388−395PubMedGoogle Scholar
  166. Stone RM, DeAngelo DJ, Klimek V et al. (2005) Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood 105:54−60PubMedGoogle Scholar
  167. Sun H, Nikolovska-Coleska Z, Yang CY et al. (2004) Structure-based design, synthesis, and evaluation of conformationally constrained mimetics of the second mitochondria-derived activator of caspase that target the X-linked inhibitor of apoptosis protein/caspase-9 interaction site. J Med Chem 47:4147−4150PubMedGoogle Scholar
  168. Tabernero J (2007) The role of VEGF and EGFR inhibition: implications for combining anti-VEGF and anti-EGFR agents. Mol Cancer Res 5:203−220PubMedGoogle Scholar
  169. Takada Y, Kobayashi Y, Aggarwal BB (2005) Evodiamine abolishes constitutive and inducible NF-kappaB activation by inhibiting IkappaBalpha kinase activation, thereby suppressing NF-kappaB-regulated antiapoptotic and metastatic gene expression, up-regulating apoptosis, and inhibiting invasion. J Biol Chem 280:17203−17212PubMedGoogle Scholar
  170. Takahashi I, Saitoh Y, Yoshida M et al. (1989) UCN-01 and UCN-02, new selective inhibitors of protein kinase C. II. Purification, physico-chemical properties, structural determination and biological activities. J Antibiot (Tokyo) 42:571−576Google Scholar
  171. Tang L, Boise LH, Dent P et al. (2000) Potentiation of 1-beta-D-arabinofuranosylcytosine-mediated mitochondrial damage and apoptosis in human leukemia cells (U937) overexpressing bcl-2 by the kinase inhibitor 7-hydroxystaurosporine (UCN-01). Biochem Pharmacol 60:1445−1456PubMedGoogle Scholar
  172. Tergaonkar V, Bottero V, Ikawa M et al. (2003) IkappaB kinase-independent IkappaBalpha degradation pathway:functional NF-kappaB activity and implications for cancer therapy. Mol Cell Biol 23:8070−8083PubMedGoogle Scholar
  173. Thomas RK, Greulich H, Yuza Y et al. (2005) Detection of oncogenic mutations in the EGFR gene in lung adenocarcinoma with differential sensitivity to EGFR tyrosine kinase inhibitors. Cold Spring Harb Symp Quant Biol 70:73−81PubMedGoogle Scholar
  174. Thorburn A (2004) Death receptor-induced cell killing. Cell Signal 16:139−144PubMedGoogle Scholar
  175. Todd DG, Mikkelsen RB, Rorrer WK et al. (1999) Ionizing radiation stimulates existing signal transduction pathways involving the activation of epidermal growth factor receptor and ERBB-3, and changes of intracellular calcium in A431 human squamous carcinoma cells. J Recept Signal Transduct Res 19:885−908PubMedGoogle Scholar
  176. Tol J, Koopman M, Rodenburg CJ et al. (2008) A randomised phase III study on capecitabine, oxaliplatin and bevacizumab with or without cetuximab in first-line advanced colorectal cancer, the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). An interim analysis of toxicity. Ann Oncol 19:734−738PubMedGoogle Scholar
  177. Tournier C, Hess P, Yang DD et al. (2000) Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science 288:870−874PubMedGoogle Scholar
  178. Ungerstedt JS, Sowa Y, Xu WS et al. (2005) Role of thioredoxin in the response of normal and transformed cells to histone deacetylase inhibitors. Proc Natl Acad Sci U S A 102:673−678PubMedGoogle Scholar
  179. Van Oosterom AT, Judson IR, Verweij J et al. (2002) Update of phase I study of imatinib (STI571) in advanced soft tissue sarcomas and gastrointestinal stromal tumors: a report of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 38 (Suppl 5):S83−S87PubMedGoogle Scholar
  180. Vermorken JB, Trigo J, Hitt R et al. (2007) Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 25:2171−2177PubMedGoogle Scholar
  181. Voigt W, Pickan V, Pfeiffer C et al. (2005) Preclinical evaluation of ZD1839 alone or in combination with oxaliplatin in a panel of human tumor cell lines: implications for clinical use. Onkologie 28:482−488PubMedGoogle Scholar
  182. Wang S, El-Deiry WS (2003) TRAIL and apoptosis induction by TNF-family death receptors. Oncogene 22:8628−8633PubMedGoogle Scholar
  183. Wang JL, Liu D, Zhang ZJ et al. (2000) Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells. Proc Natl Acad Sci U S A 97:7124−7129PubMedGoogle Scholar
  184. Weisberg E, Boulton C, Kelly LM et al. (2002) Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell 1:433−443PubMedGoogle Scholar
  185. Whittaker SR, Walton MI, Garrett MD et al. (2004) The cyclin-dependent kinase inhibitor CYC202 (R-roscovitine) inhibits retinoblastoma protein phosphorylation, causes loss of Cyclin D1, and activates the mitogen-activated protein kinase pathway. Cancer Res 64:262−272PubMedGoogle Scholar
  186. Wijermans PW, Lubbert M, Verhoef G et al. (2005) An epigenetic approach to the treatment of advanced MDS; the experience with the DNA demethylating agent 5-aza-2'-deoxycytidine (decitabine) in 177 patients. Ann Hematol 84 (Suppl 1):9−17PubMedGoogle Scholar
  187. Willers H, Held KD (2006) Introduction to clinical radiation biology. Hematol Oncol Clin North Am 20:1−24PubMedGoogle Scholar
  188. Workman P (2004) Altered states: selectively drugging the Hsp90 cancer chaperone. Trends Mol Med 10:47−51PubMedGoogle Scholar
  189. Xia Z, Dickens M, Raingeaud J et al. (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270:1326−1331PubMedGoogle Scholar
  190. Yacoub A, McKinstry R, Hinman D et al. (2003) Epidermal growth factor and ionizing radiation up-regulate the DNA repair genes XRCC1 and ERCC1 in DU145 and LNCaP prostate carcinoma through MAPK signaling. Radiat Res 159:439−452PubMedGoogle Scholar
  191. Yacoub A, Park MA, Hanna D et al. (2006) OSU-03012 promotes caspase-independent but PERK-, cathepsin B-, BID-, and AIF-dependent killing of transformed cells. Mol Pharmacol 70:589−603PubMedGoogle Scholar
  192. Yang JC, Haworth L, Sherry RM et al. (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427−434PubMedGoogle Scholar
  193. Yu X, Guo ZS, Marcu MG et al. (2002) Modulation of p53, ErbB1, ErbB2, and Raf-1 expression in lung cancer cells by depsipeptide FR901228. J Natl Cancer Inst 94:504−513PubMedGoogle Scholar
  194. Yu C, Rahmani M, Conrad D et al. (2003a) The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571. Blood 102:3765−3774Google Scholar
  195. Yu C, Rahmani M, Almenara J et al. (2003b) Histone deacetylase inhibitors promote STI571-mediated apoptosis in STI571-sensitive and -resistant Bcr/Abl+ human myeloid leukemia cells. Cancer Res 63:2118−2126Google Scholar
  196. Yu C, Rahmani M, Dent P et al. (2004) The hierarchical relationship between MAPK signaling and ROS generation in human leukemia cells undergoing apoptosis in response to the proteasome inhibitor Bortezomib. Exp Cell Res 295:555−566PubMedGoogle Scholar
  197. Yu C, Dasmahapatra G, Dent P et al. (2005) Synergistic interactions between MEK1/2 and histone deacetylase inhibitors in BCR/ABL+ human leukemia cells. Leukemia 19:1579−1589PubMedGoogle Scholar
  198. Zangari M, Esseltine D, Lee CK et al. (2005) Response to bortezomib is associated to osteoblastic activation in patients with multiple myeloma. Br J Haematol 131:71−73PubMedGoogle Scholar
  199. Zhao B, Bower MJ, McDevitt PJ et al. (2002) Structural basis for Chk1 inhibition by UCN-01. J Biol Chem 277:46609−46615PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Shiyu Song
    • 1
  • Paul Dent
    • 2
  • Steven Grant
    • 3
  1. 1.Department of Radiation Oncology, Massey Cancer CenterVirginia Commonwealth University Health SystemRichmondUSA
  2. 2.Department of Biochemistry, Massey Cancer CenterVirginia Commonwealth University Health SystemRichmondUSA
  3. 3.Departments of Medicine and Biochemistry, Massey Cancer CenterVirginia Commonwealth University Health SystemRichmondUSA

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