Gastric cancer in the era of molecularly targeted agents: current drug development strategies

Review

Abstract

Gastric cancer is the second most common cause of cancer death worldwide with approximately one million cases diagnosed annually. Despite considerable improvements in surgical techniques, innovations in clinical diagnostics and the development of new chemotherapy regimens, the clinical outcome for patients with advanced gastric cancer and cancer of the GEJ is generally poor with 5-year survival rates ranging between 5 and 15%. The understanding of cancer relevant events has resulted in new therapeutic strategies, particularly in developing of new molecular targeted agents. These agents have the ability to target a variety of cancer relevant receptors and downstream pathways including the epidermal growth factor receptor (EGFR), the vascular endothelial growth factor receptor (VEGFR), the insulin-like growth factor receptor (IGFR), the c-Met pathway, cell-cycle pathways, and down-stream signalling pathways such as the Akt-PI3k-mTOR pathway. In the era of new molecularly targeted agents this review focuses on recent developments of targeting relevant pathways involved in gastric cancer and cancer of the GEJ.

Keywords

Molecularly targeted agents Gastric cancer Gastroesophageal cancer GEJ 

References

  1. Amemiya H, Kono K, Itakura J et al (2002) C-Met expression in gastric cancer with liver metastasis. Oncology 63(3):286–296. doi:10.1159/000065477 PubMedCrossRefGoogle Scholar
  2. Attard G, Fong PC, Molife R et al (2006) Phase I trial involving the pharmacodynamic (PD) study of circulating tumour cells, of CP-751, 871 (C), a monoclonal antibody against the insulin-like growth factor 1 receptor (IGF-1R), with docetaxel (D) in patients (p) with advanced cancer. J Clin Oncol 24:3023Google Scholar
  3. Bae SH, Ryoo HM, Kim MK et al (2008) Effects of the proteasome inhibitor bortezomib alone and in combination with chemotherapeutic agents in gastric cancer cell lines. Oncol Rep 19(4):1027–1032PubMedGoogle Scholar
  4. Bang Y, Kang Y, Kang W et al (2007) Sunitinib as second-line treatment for advanced gastric cancer: preliminary results from a phase II study. J Clin Oncol 25:4603. doi:10.1200/JCO.2007.10.8688 CrossRefGoogle Scholar
  5. Bang Y, Chung H, Sawaki A et al (2008) HER2-positivity rates in advanced gastric cancer (GC): results from a large international phase III trial. J Clin Oncol 26:4526Google Scholar
  6. Bolden JE, Peart MJ, Johnston RW (2006) Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5(9):769–784. doi:10.1038/nrd2133 PubMedCrossRefGoogle Scholar
  7. Bramhall SR, Hallissey MT, Whiting J et al (2002) Marimastat as maintenance therapy for patients with advanced gastric cancer: a randomised trial. Br J Cancer 86(12):1864–1870. doi:10.1038/sj.bjc.6600310 PubMedCrossRefGoogle Scholar
  8. Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9:653–660. doi:10.1038/nm0603-653 PubMedCrossRefGoogle Scholar
  9. Carpenter G, Cohen S (1990) Epidermal growth factor. J Biol Chem 265:7709–7712PubMedGoogle Scholar
  10. Cauwe B, Van den Steen PE, Opdenakker G (2007) The biochemical, biological, and pathological kaleidoscope of cell surface substrates processed by matrix metalloproteinases. Crit Rev Biochem Mol Biol 42(3):113–185. doi:10.1080/10409230701340019 PubMedCrossRefGoogle Scholar
  11. Cejka D, Preusser M, Woehrer A et al. (2008) Everolimus (RAD001) and anti-angiogenic cyclophosphamide show long-term control of gastric cancer growth in vivo. Cancer Biol Ther 7(9) (epub ahead of print)Google Scholar
  12. Cheema HS, Motwani MV et al. (2004) Suberoylanilide Hydroxamic Acid (SAHA), a histone deacetylase (HDAC) inhibitor, induces a unique mitotic effect and potentiates flavopiridol (F) induced apoptosis. Proc Am Assoc Cancer Res 45: 2443Google Scholar
  13. Cohenuram MK, Lacy J (2008) FOLFOX6 and bevacizumab (FOLFOX6/B) for metastatic esophageal (E), gastroesophageal (GE), and gastric (G) adenocarcinoma: a single institution’s initial clinical experience. Proc GI ASCO: 74Google Scholar
  14. Cortés-Funes H, Rivera F, Alés I et al (2007) Phase II of trastuzumab and cisplatin in patients (pts) with advanced gastric cancer (AGC) with HER2/neu overexpression/amplification. J Clin Oncol 25:4613Google Scholar
  15. Dar AA, Zaika A, Piazuela MB et al (2008) Frequent overexpression of aurora kinase A in upper gastrointestinal adenocarcinomas correlates with potent antiapoptotic functions. Cancer 112(8):1688–1698. doi:10.1002/cncr.23371 PubMedCrossRefGoogle Scholar
  16. de Mingo M, Morán A, Sánchez-Pernaute A et al (2007) Expression of MMP-9 and TIMP-1 as prognostic markers in gastric carcinoma. Hepatogastroenterology 54(73):315–319PubMedGoogle Scholar
  17. Dragovich T, McCoy S, Fenoglio-Preiser CM et al (2006) Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127. J Clin Oncol 24(30):4922–4927. doi:10.1200/JCO.2006.07.1316 PubMedCrossRefGoogle Scholar
  18. Eskens FA, Mom CH, Planting AS et al (2008) A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours. Br J Cancer 98(1):80–85. doi:10.1038/sj.bjc.6604108 PubMedCrossRefGoogle Scholar
  19. Fujita T, Doihara H, Washio K et al (2007) Antitumor effects and drug interactions of the proteasome inhibitor bortezomib (PS341) in gastric cancer cells. Anticancer Drugs 18(6):677–686. doi:10.1097/CAD.0b013e32808bf9d8 PubMedCrossRefGoogle Scholar
  20. Gong SJ, Jin CJ, Rha SY et al (2004) Growth inhibitory effects of trastuzumab and chemotherapeutic drugs in gastric cancer cell lines. Cancer Lett 214(2):215–224. doi:10.1016/j.canlet.2004.04.029 PubMedCrossRefGoogle Scholar
  21. Grimber A, Cohen P (2000) Role of insulin-like growth factor and their binding proteins in growth control and carcinogenesis. J Cell Physiol 183:1–9. doi:10.1002/(SICI)1097-4652(200004)183:1<1::AID-JCP1>3.0.CO;2-J CrossRefGoogle Scholar
  22. Haluska P, Shaw H, Batzel GN et al (2007) Phase I dose escalation study of the anti-IGF-1R monoclonal antibody CP-751, 871 in patients with refractory solid tumors. J Clin Oncol 25:3586Google Scholar
  23. Hammad N, Philip PA, Shields AF et al. (2008) A phase II study of bevacizumab, docetaxel, and oxaliplatin in gastric and gastroesophageal junction (GEJ) cancer. Proc GI ASCO: 30Google Scholar
  24. Han Z, Wu K, Shen H et al (2008) Akt1/protein kinase B alpha is involved in gastric cancer progression and cell proliferation. Dig Dis Sci 53(7):1801–1810. doi:10.1007/s10620-007-9824-2 PubMedCrossRefGoogle Scholar
  25. Han SW, Oh DY, Im SA et al (2009) Phase II study and biomarker analysis of cetuximab in combination with modified FOLFOX6 in advanced gastric cancer. Br J Cancer 100(2):298–304. doi:10.1038/sj.bjc.6604861 PubMedCrossRefGoogle Scholar
  26. Hattori Y, Itoh H, Uchino S et al (1996) Immunohistochemical detection of K-sam protein in stomach cancer. Clin Cancer Res 2(8):1373–1381PubMedGoogle Scholar
  27. Hecht JR, Urba SG, Koehler M et al. (2008) Lapatinib monotherapy in recurrent upper gastrointestinal malignancy: phase II efficacy and biomarker analyses. Proc GI ASCO: 43Google Scholar
  28. Hecht JR, Mitchell E, Chidiac T et al (2009) A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol 27(5):672–680. doi:10.1200/JCO.2008.19.8135 PubMedCrossRefGoogle Scholar
  29. Hinoda Y, Sasaki S, Ishida T et al (2004) Monoclonal antibodies as effective therapeutic agents for solid tumors. Cancer Sci 96:443–446Google Scholar
  30. Hirata A, Ogawa S, Kometani T et al (2002) ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase. Cancer Res 62(9):2554–2560PubMedGoogle Scholar
  31. Inoue T, Kataoka H, Goto K et al (2004) Activation of c-Met (hepatocyte growth factor receptor) in human gastric cancer tissue. Cancer Sci 95(10):803–808. doi:10.1111/j.1349-7006.2004.tb02185.x PubMedCrossRefGoogle Scholar
  32. Iqbal S, Goldman B, Lenz HJ et al (2007) S0413: a phase II SWOG study of GW572016 (lapatinib) as first line therapy in patients (pts) with advanced or metastatic gastric cancer. J Clin Oncol 25:4621Google Scholar
  33. Iwamoto J, Mizokami Y, Takahashi K et al (2008) The effects of cyclooxygenase2-prostaglandinE2 pathway on Helicobacter pylori-induced urokinase-type plasminogen activator system in the gastric cancer cells. Helicobacter 13(3):174–182. doi:10.1111/j.1523-5378.2008.00597.x PubMedCrossRefGoogle Scholar
  34. Jang YJ, Kim YS, Kim WH et al (2006) Oncogenic effect of Polo-like kinase 1 expression in human gastric carcinomas. Int J Cancer 29(3):589–594Google Scholar
  35. Jhawer MP, Ilson D, Robinson E et al. (2008) Interim results of a phase II study of modified docetaxel, cisplatin, fluorouracil (mDCF), and bevacizumab (BEV) in patients with metastatic gastroesophageal (GE) adenocarcinoma. Proc GI ASCO: 109Google Scholar
  36. Jhawer MP, Kindler HL, Wainberg ZA et al (2008b) Preliminary activity of XL880, a dual MET/VEGFR2 inhibitor, in MET amplified poorly differentiated gastric cancer (PDGC): interim results of a multicenter phase II study. J Clin Oncol 26:4572. doi:10.1200/JCO.2007.15.5655 CrossRefGoogle Scholar
  37. Jones HE, Gee JMW, Hutcheson IR et al (2006) Growth factor receptor interplay and resistance in cancer. Endocr Relat Cancer 13(Suppl 1):S45–S51. doi:10.1677/erc.1.01275 PubMedCrossRefGoogle Scholar
  38. Kamada K, Yamada Y, Hirao T et al (2004) Amplification/overexpression of Aurora-A in human gastric carcinoma: potential role in differentiated type gastric carcinogenesis. Oncol Rep 12(3):593–599PubMedGoogle Scholar
  39. Karayiannakis AJ, Syrigos KN, Polychronidis A et al (2002) Circulating VEGF levels in the serum of gastric cancer patients: correlation with pathological variables, patient survival, and tumor surgery. Ann Surg 236(1):37–42. doi:10.1097/00000658-200207000-00007 PubMedCrossRefGoogle Scholar
  40. Kim JW, Kim HP, Im SA et al. (2008) The growth inhibitory effect of lapatinib, a dual inhibitor of EGFR and HER2 tyrosine kinase, in gastric cancer cell lines. Cancer Lett (e-pub ahead of print)Google Scholar
  41. Kuwano T, Nakao S, Yamamoto H (2004) Cyclooxygenase 2 is a key enzyme for inflammatory cytokine-induced angiogenesis. FASEB J 18(2):300–310. doi:10.1096/fj.03-0473com PubMedCrossRefGoogle Scholar
  42. Lang SA, Klein D, Moser C et al (2007a) Inhibition of heat shock protein 90 impairs epidermal growth factor-mediated signaling in gastric cancer cells and reduces tumor growth and vascularization in vivo. Mol Cancer Ther 6(3):1123–1132. doi:10.1158/1535-7163.MCT-06-0628 PubMedCrossRefGoogle Scholar
  43. Lang SA, Gaumann A, Koehl GE et al (2007b) Mammalian target of rapamycin is activated in human gastric cancer and serves as a target for therapy in an experimental model. Int J Cancer 120(8):1803–1810. doi:10.1002/ijc.22442 PubMedCrossRefGoogle Scholar
  44. Lax AJ, Thomas W (2002) How bacteria could cause cancer: one step at a time. Trends Microbiol 10(6):293–299. doi:10.1016/S0966-842X(02)02360-0 PubMedCrossRefGoogle Scholar
  45. Lordick F, Lorenzen S, Hegewisch-Becker S et al (2007) Cetuximab plus weekly oxaliplatin/5FU/FA (FUFOX) in 1st line metastatic gastric cancer. Final results from a multicenter phase II study of the AIO upper GI study group. J Clin Oncol 26:4526Google Scholar
  46. Macarulla T, Ramos FJ, Tabernero J (2008) Aurora kinase family: a new target for anticancer drug. Recent Patents Anticancer Drug Discov 3(2):114–122CrossRefGoogle Scholar
  47. Mani A, Gelmann EP (2005) The Ubiquitin-Proteasome pathway and its role in cancer. J Clin Oncol 23(21):4776–4789. doi:10.1200/JCO.2005.05.081 PubMedCrossRefGoogle Scholar
  48. Mann JR, Backlund MG, DuBois RN (2005) Mechanisms of disease: inflammatory mediators and cancer prevention. Nat Clin Pract Oncol 2(4):202–210. doi:10.1038/ncponc0140 PubMedCrossRefGoogle Scholar
  49. Marks PA, Jiang X (2005) Histone deacetylase inhibitors in programmed cell death and cancer therapy. Cell Cycle 4(4):549–551PubMedGoogle Scholar
  50. Marumoto T, Hirota T, Morisaki T et al (2002) Roles of aurora-A kinase in mitotic entry and G2 checkpoint in mammalian cells. Genes Cells 7:1173–1182. doi:10.1046/j.1365-2443.2002.00592.x PubMedCrossRefGoogle Scholar
  51. Matsubara J, Yamada Y, Hirashima Y et al (2008) Impact of insulin-like growth factor type 1 receptor, epidermal growth factor receptor, and HER2 expressions on outcomes of patients with gastric cancer. Clin Cancer Res 14(10):3022–3029. doi:10.1158/1078-0432.CCR-07-1898 PubMedCrossRefGoogle Scholar
  52. Maulik G, Shrikhande A, Kijima T et al (2002) Role of the hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition. Cytokine Growth Factor Rev 13(1):41–59. doi:10.1016/S1359-6101(01)00029-6 PubMedCrossRefGoogle Scholar
  53. McCarty MF, Wey J, Stoeltzing O et al (2004) ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor with additional activity against epidermal growth factor receptor tyrosine kinase, inhibits orthotopic growth and angiogenesis of gastric cancer. Mol Cancer Ther 3(9):1041–1048PubMedGoogle Scholar
  54. Miremadi A, Oestergaard MZ, Pharoah PD et al (2007) Cancer genetics of epigenetic genes. Hum Mol Genet 16(1):R28–R49. doi:10.1093/hmg/ddm021 PubMedCrossRefGoogle Scholar
  55. Moehler M, Hartmann JT, Lordick F et al. (2009) Sunitinib in patients with chemorefractory metastatic gastric cancer: preliminary results of an open-label, prospective non-randomised multicentre AIO Phase II trial. Proc GI ASCO: 61Google Scholar
  56. Morgensztern D, McLeod HL (2005) PI3K/Akt/mTOR pathway as a target for cancer therapy. Anticancer Drugs 16(8):797–803. doi:10.1097/01.cad.0000173476.67239.3b PubMedCrossRefGoogle Scholar
  57. Motzer RJ, Hutson TE, Tomczak P et al (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356(2):115–124. doi:10.1056/NEJMoa065044 PubMedCrossRefGoogle Scholar
  58. Muro K, Boku N, Yamada Y et al (2008) Multicenter phase II study of RAD001 for previously treated metastatic gastric cancer (MGC): preliminary results. J Clin Oncol 26:4541Google Scholar
  59. Nakajima M, Sawada H, Yamada Y et al (2000) The prognostic significance of amplification and overexpression of c-met and c-erb B-2 in human gastric carcinomas. Cancer 85:1894–1902Google Scholar
  60. Nakamura K, Yashiro M, Matsuoka T et al (2006) A novel molecular targeting compound as K-samII/FGF-R2 phosphorylation inhibitor, Ki23057, for Scirrhous gastric cancer. Gastroenterology 131(5):1530–1541. doi:10.1053/j.gastro.2006.08.030 PubMedCrossRefGoogle Scholar
  61. Ocean AJ, Schnoll-Sussman F, Chen X et al. (2007) Phase II study of PS-341 (VELCADE, bortezomib) with or without irinotecan in patients (pts) with advanced gastric adenocarcinomas (AGA). Proc GI ASCO: 45Google Scholar
  62. Oki E, Baba H, Tokunaga E et al (2005) Akt phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer. Int J Cancer 117(3):376–380. doi:10.1002/ijc.21170 PubMedCrossRefGoogle Scholar
  63. Park JH, Jung Y, Kim TY et al (2004) Class I histone deacetylase-selective novel synthetic inhibitors potently inhibit human tumor proliferation. Clin Cancer Res 10(15):5271–5281. doi:10.1158/1078-0432.CCR-03-0709 PubMedCrossRefGoogle Scholar
  64. Pinto C, Di Fabio F, Siena S et al (2007) Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma (FOLCETUX study). Ann Oncol 18(3):510–517. doi:10.1093/annonc/mdl459 PubMedCrossRefGoogle Scholar
  65. Pinto C, Di Fabio F, Barone C et al. (2008) Phase II study of cetuximab in combination with cisplatin/docetaxel as first-line treatment in patients with unresectable/metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma (DOCETUX Study): preliminary results. Proc GI ASCO: 34Google Scholar
  66. Presta LG, Chen H, O’Connor SJ et al (1997) Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 57:4593–4599PubMedGoogle Scholar
  67. Rao S, Starling N, Cunningham D et al. (2008) Phase I study of epirubicin, cisplatin and capecitabine plus matuzumab in previously untreated patients with advanced oesophagogastric cancer. Br J Cancer (epub ahead of print)Google Scholar
  68. Rojo F, Tabernero J, Albanell J et al (2006) Pharmacodynamic studies of gefitinib in tumor biopsy specimens from patients with advanced gastric carcinoma. J Clin Oncol 24(26):4309–4316. doi:10.1200/JCO.2005.04.2424 PubMedCrossRefGoogle Scholar
  69. Saltz LB, Meropol NJ, Loehrer PJ et al (2004) Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22:1201–1208. doi:10.1200/JCO.2004.10.182 PubMedCrossRefGoogle Scholar
  70. Saltz LB, Lenz HJ, Kindler HL et al (2007) Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 Study. J Clin Oncol 25:4557–4561. doi:10.1200/JCO.2007.12.0949 PubMedCrossRefGoogle Scholar
  71. Schwartz GK, Ilson D, Saltz L et al (2001) Phase II study of the cyclin-dependent kinase inhibitor flavopiridol administered to patients with advanced gastric carcinoma. J Clin Oncol 19(7):1985–1992PubMedGoogle Scholar
  72. Senderowicz AM (2000) Small molecule modulators of cyclin-dependent kinases for cancer therapy. Oncogene 19(56):6600–6606. doi:10.1038/sj.onc.1204085 PubMedCrossRefGoogle Scholar
  73. Shah MA, Ramanathan RK, Ilson DH et al (2006) Multicenter phase II study of irinotecan, cisplatin, and bevacizumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol 24(33):5201–5206. doi:10.1200/JCO.2006.08.0887 PubMedCrossRefGoogle Scholar
  74. Song J, Noh JH, Lee JH et al (2005) Increased expression of histone deacetylase 2 is found in human gastric cancer. APMIS 113(4):264–268. doi:10.1111/j.1600-0463.2005.apm_04.x PubMedCrossRefGoogle Scholar
  75. Stein A, Al-Batran SE, Arnold D et al. (2007) Cetuximab with irinotecan as salvage therapy in heavily pretreated patients with metastatic gastric cancer. Proc GI ASCO: 47Google Scholar
  76. Sun W, Powell ME, O’Dwyer P et al (2008) A phase II study: combination of sorafenib with docetaxel and cisplatin in the treatment of metastatic or advanced unresectable gastric and gastroesophageal junction (GEJ) adenocarcinoma (ECOG 5203). J Clin Oncol 26:4535CrossRefGoogle Scholar
  77. Tahara E (2004) Genetic pathways of two types of gastric cancer. IARC Sci Publ 157:327–349PubMedGoogle Scholar
  78. Takai N, Hamanaka R, Yoshimatsu J et al (2005) Polo-like kinases (Plks) and cancer. Oncogene 24(2):287–291. doi:10.1038/sj.onc.1208272 PubMedCrossRefGoogle Scholar
  79. Tanner M, Hollmen M, Junttila TT et al (2005) Amplification of HER-2 in gastric carcinoma: association with topoisomerase II alpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol 16:273–278. doi:10.1093/annonc/mdi064 PubMedCrossRefGoogle Scholar
  80. Tebbutt NC, Sourjina T, Strickland AH et al (2008) ATTAX2: docetaxel plus cetuximab as second-line treatment for docetaxel-refractory oesophago-gastric cancer—final results of a multicentre phase II trial by the AGITG. J Clin Oncol 26:15554Google Scholar
  81. Thomas JP, Tutsch KD, Cleary JF et al (2002) Phase I clinical and pharmacokinetic trial of the cyclin-dependent kinase inhibitor flavopiridol. Cancer Chemother Pharmacol 50(6):465–472. doi:10.1007/s00280-002-0527-2 PubMedCrossRefGoogle Scholar
  82. Tierney GM, Griffin NR, Stuart RC et al (1999) A pilot study of the safety and effects of the matrix metalloproteinase inhibitor marimastat in gastric cancer. Eur J Cancer 35(4):563–568. doi:10.1016/S0959-8049(99)00007-6 PubMedCrossRefGoogle Scholar
  83. Tol J, Koopman M, Cats A et al. (2009) Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 360(6):563–572Google Scholar
  84. Tortora G, Ciardiello F, Gasparini G (2008) Combined targeting of EGFR-dependent and VEGF-dependent pathways: rationale, preclinical studies and clinical applications. Nat Clin Pract Oncol 5(9):521–530. doi:10.1038/ncponc1161 PubMedCrossRefGoogle Scholar
  85. Tsutsumi S, Neckers L (2007) Extracellular heat shock protein 90: a role for a molecular chaperone in cell motility and cancer metastasis. Cancer Sci 98(10):1536–1539. doi:10.1111/j.1349-7006.2007.00561.x PubMedCrossRefGoogle Scholar
  86. Van Cutsem E, Peeters M, Siena S et al (2007) Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25(13):1658–1664. doi:10.1200/JCO.2006.08.1620 PubMedCrossRefGoogle Scholar
  87. Wada N, Otani Y, Kubota T et al (2003) Reduced angiogenesis in peritoneal dissemination of gastric cancer through gelatinase inhibition. Clin Exp Metastasis 20(5):431–435. doi:10.1023/A:1025453500148 PubMedCrossRefGoogle Scholar
  88. Wang HK (2001) Flavopiridol. National Cancer Institute. Curr Opin Invest Drugs 2(8):1149–1155Google Scholar
  89. Wang WH, Huang JQ, Zheng GF et al (2003) Non-steroidal anti-inflammatory drug use and the risk of gastric cancer: a systematic review and meta-analysis. J Natl Cancer Inst 95(23):1784–1791PubMedGoogle Scholar
  90. Weichert W, Ullrich A, Schmidt M et al (2006) Expression patterns of polo-like kinase 1 in human gastric cancer. Cancer Sci 97(4):271–276. doi:10.1111/j.1349-7006.2006.00170.x PubMedCrossRefGoogle Scholar
  91. Weichert W, Röske A, Gekeler V et al (2008) Association of patterns of class I histone deacetylase expression with patient prognosis in gastric cancer: a retrospective analysis. Lancet Oncol 9(2):139–148. doi:10.1016/S1470-2045(08)70004-4 PubMedCrossRefGoogle Scholar
  92. Woell E, Greil R, Eisterer W et al (2008) Oxaliplatin, irinotecan and cetuximab in advanced gastric cancer: first results of a multicenter phase II trial (AGMT Gastric-2). J Clin Oncol 26:15587Google Scholar
  93. Yap TA, Harris D, Barriuso J et al (2008) Phase I trial to determine the dose range for the c-Met inhibitor ARQ 197 that inhibits c-Met and FAK phosphorylation, when administered by an oral twice-a-day schedule. J Clin Oncol 26:3584Google Scholar
  94. Zou XM, Li YL, Wang H et al (2008) Gastric cancer cell lines induced by trichostatin A. World J Gastroenterol 14(30):4810–4815. doi:10.3748/wjg.14.4810 PubMedCrossRefGoogle Scholar
  95. Zucker S, Cao J, Chen WT (2000) Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. Oncogene 19(56):6642–6650. doi:10.1038/sj.onc.1204097 PubMedCrossRefGoogle Scholar
  96. Zuo DS, Dai J, Bo AH et al (2003) Significance of expression of heat shock protein90alpha in human gastric cancer. World J Gastroenterol 9(11):2616–2618PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.The Medical Professorial Unit, Prince of Wales Medical SchoolUniversity of New South WalesSydneyAustralia

Personalised recommendations