Opportunities for targeted therapies in hepatocellular carcinoma

Journal of Clinical Oncology

Volumn 23, Issue 31, 2005, Pages 8093-8108

  Thomas, Melanie B ^a   Abbruzzese, James L ^a  

^a UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 (2 CHLORO 4 IODOANILINO) N CYCLOPROPYLMETHOXY 3,4 DIFLUOROBENZAMIDE; 3 BENZYL 7 CYANO 2,3,4,5 TETRAHYDRO 1 (1H IMIDAZOL 4 YLMETHYL) 4 (2 THIENYLSULFONYL) 1H 1,4 BENZODIAZEPINE; 6 (4 HYDROXYPHENYL) 4 (ALPHA METHYLBENZYLAMINO) 7H PYRROLO[2,3 D]PYRIMIDINE; 6 [4 (4 ETHYL 1 PIPERAZINYLMETHYL)PHENYL] 4 (ALPHA METHYLBENZYLAMINO) 7H PYRROLO[2,3 D]PYRIMIDINE; 7 HYDROXYSTAUROSPORINE; BEVACIZUMAB; BORTEZOMIB; CANERTINIB; CETUXIMAB; CGP 69846A; ERLOTINIB; EVEROLIMUS; FLAVOPIRIDOL; GEFITINIB; GROWTH FACTOR RECEPTOR; ISIS 2503; ISIS 3521; MANUMYCIN; MATUZUMAB; N (2,3 DIHYDROXYPROPOXY) 3,4 DIFLUORO 2 (2 FLUORO 4 IODOANILINO)BENZAMIDE; OBLIMERSEN; ONYX 015; PANITUMUMAB; PRINOMASTAT; PROTEIN FARNESYLTRANSFERASE INHIBITOR; PROTEIN P53; SORAFENIB; TEMSIROLIMUS; TIPIFARNIB; UDF 1; UNCLASSIFIED DRUG; UNINDEXED DRUG; VATALANIB;

ANGIOGENESIS; CANCER SURGERY; GENE MUTATION; HEPATITIS C; HUMAN; LIVER CARCINOGENESIS; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; LIVER TRANSPLANTATION; NONHUMAN; PATHOGENESIS; PREVALENCE; PRIORITY JOURNAL; REVIEW; UNITED STATES; LIVER TUMOR; MULTIMODALITY CANCER THERAPY; PATHOLOGY; TREATMENT OUTCOME;

CARCINOMA, HEPATOCELLULAR; COMBINED MODALITY THERAPY; HUMANS; LIVER NEOPLASMS; TREATMENT OUTCOME;

EID: 32944480899     PISSN: 0732183X     EISSN: None     Source Type: Journal    
DOI: 10.1200/JCO.2004.00.1537     Document Type: Review

References (205)

1. Ferlay J BF, Pisani P, Parkin DM: GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide, IARC Cancer Base (ed No. 5, Version 2). Lyon, IARC Press, 2004
2. Jemal A, Murray T, Ward E, et al: Cancer statistics, 2005. CA Cancer J Clin 55:10-30, 2005
3. Smith RA, Cokkinides V, Eyre HJ: American Cancer Society Guidelines for the Early Detection of Cancer, 2005. CA Cancer J Clin 55:31-44, 55-56, 2005
4. El-Serag HB, Davila JA, Petersen NJ, et al: The continuing increase in the incidence of hepatocellular carcinoma in the United States: An update. Ann Intern Med 139:817-823, 2003
5. El-Serag HB, Mason AC: Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 340:745-750, 1999
6. Nair S, Mason A, Eason J, et al: Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis? Hepatology 36:150-155, 2002
7. Powell EE, Jonsson JR, Clouston AD: Steatosis: Co-factor in other liver diseases. Hepatology 42:5-13, 2005
8. Umeda T, Hino O: Molecular aspects of human hepatocarcinogenesis mediated by inflammation: From hypercarcinogenic state to normo- or hypo carcinogenic state. Oncology 62 Suppl 138-42, 2002
9. Mantovani A: Cancer: Inflammation by remote control. Nature 435:752-753, 2005
10. Curtey SA, Izzo F, Ellis LM, et al: Radiofrequency ablation of hepatocellular cancer in 110 patients with cirrhosis. Ann Surg 232:381-391, 2000
11. Akriviadis EA, Llovet JM, Efremidis SC. et al: Hepatocellular carcinoma. Br J Surg 85:1319-1331, 1998
12. Bergsland EK, Venook AP: Hepatocellular carcinoma. Curr Opin Oncol 12:357-361, 2000
13. Nakakura EK, Choti MA: Management of hepatocellular carcinoma. Oncology (Williston Park) 14:1085-1102, 2000
14. Nagasue N, Kohno H, Chang YC, et al: Liver resection for hepatocellular carcinoma. Results of 229 consecutive patients during 11 years. Ann Surg 217:375-384, 1993
15. Yamamoto J, Kosuge T, Takayama T, et al: Recurrence of hepatocellular carcinoma after surgery. Br J Surg 83:1219-1222, 1996
16. Simonetti RG, Liberati A, Angiolini C, et al: Treatment of hepatocellular carcinoma: A systematic review of randomized controlled trials. Ann Oncol 8:117-136, 1997
17. Sheu JC: Molecular mechanism of hepatocarcinogenesis. J Gastroenterol Hepatol 12: S309-S313, 1997
18. Thorgeirsson SS, Grisham JW: Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 31:339-346, 2002
19. Grisham JW: Molecular Genetic Alterations in Primary Hepatocellular Neoplasms. Towtowa, NJ, Humana Press, 2002
20. Nagai H, Pineau P, Tiollais P, et al: Comprehensive allelotyping of human hepatocellular carcinoma. Oncogene 14:2927-2933, 1997
21. Lee JS, Grisham JW, Thorgeirsson SS: Comparative functional genomics for identifying models of human cancer. Carcinogenesis 26:1013-1020, 2005
22. Theise ND, Park YN, Kojiro M: Dysplastic nodules and hepatocarcinogenesis. Clin Liver Dis 6:497-512, 2002
23. Fausto N, Webber EM: Control of liver growth. Crit Rev Eukaryot Gene Expr 3:117-135, 1993
24. Fujimori M, Tokino T, Hino O, et al: Allelotype study of primary hepatocellular carcinoma. Cancer Res 51:89-93, 1991
25. Tsuda H, Oda T, Sakamoto M, et al: Different pattern of chromosomal allele loss in multiple hepatocellular carcinomas as evidence of their multifocal origin. Cancer Res 52:1504-1509, 1992
26. Feitelson MA, Sun B, Satiroglu Tufan NL, et al: Genetic mechanisms of hepatocarcinogenesis. Oncogene 21:2593-2604, 2002
27. Unsal H, Yakicier C, Marcais C, et al: Genetic heterogeneity of hepatocellular carcinoma. Proc Natl Acad Sci U S A 91:822-826, 1994
28. Murakami Y, Hayashi K, Hirohashi S, et al: Aberrations of the tumor suppressor p53 and retinoblastoma genes in human hepatocellular carcinomas. Cancer Res 51:5520-5525, 1991
29. Nishida N, Fukuda Y, Kokuryu H, et al: Accumulation of allelic loss on arms of chromosomes 13q, 16q and 17p in the advanced stages of human hepatocellular carcinoma. Int J Cancer 51:862-868, 1992
30. Nishida N, Fukuda Y, Kokuryu H, et al: Role and mutational heterogeneity of the p53 gene in hepatocellular carcinoma. Cancer Res 53:368-372, 1993
31. Kazachkov Y, Khaoustov V, Yoffe B, et al: p53 abnormalities in hepatocellular carcinoma from United States patients: Analysis of all 11 exons. Carcinogenesis 17:2207-2212, 1996
32. Vautier G, Bomford AB, Portmann BC, et al: p53 mutations in british patients with hepatocellular carcinoma: Clustering in genetic hemochromatosis. Gastroenterology 117:154-160, 1999
33. Piao Z, Kim H, Jeon BK, et al: Relationship between loss of heterozygosity of tumor suppressor genes and histologic differentiation in hepatocellular carcinoma. Cancer 80:865-872, 1997
34. Ponchel F, Puisieux A, Tabone E, et al: Hepatocarcinoma-specific mutant p53-249ser induces mitotic activity but has no effect on transforming growth factor beta 1-mediated apoptosis. Cancer Res 54:2064-2068, 1994
35. Cerutti P, Hussain P, Pourzand C, et al: Mutagenesis of the H-ras protooncogene and the p53 tumor suppressor gene. Cancer Res 54:19343-1938s, 1994
36. Kishimoto Y, Shiota G, Kamisaki Y, et al: Loss of the tumor suppressor p53 gene at the liver cirrhosis stage in Japanese patients with hepatocellular carcinoma. Oncology 54:304-310, 1997
37. Lebedeva IV, Su ZZ, Sarkar D, et al: Restoring apoptosis as a strategy for cancer gene therapy: Focus on p53 and mda-7. Semin Cancer Biol 13:169-178, 2003
38. Simpson KJ, Lukacs NW, Colletti L, et al: Cytokines and the liver. J Hepatol 27:1120-1132, 1997
39. Anthony PP, Ishak KG, Nayak NC, et al: The morphology of cirrhosis. Recommendations on definition, nomenclature, and classification by a working group sponsored by the World Health Organization. J Clin Pathol 31:395-414, 1978
40. Borzio M, Trere D, Borzio F, et al: Hepatocyte proliferation rate is a powerful parameter for predicting hepatocellular carcinoma development in liver cirrhosis. Mol Pathol 51:96-101, 1998
41. Hino O, Kajino K, Umeda T, et al: Understanding the hypercarcinogenic state in chronic hepatitis: A clue to the prevention of human hepatocellular carcinoma. J Gastroenterol 37:883-887, 2002
42. Le Bail B, Faouzi S, Boussarie L, et al: Extracellular matrix composition and integrin expression in early hepatocarcinogenesis in human cirrhotic liver. J Pathol 181:330-337, 1997
43. Okazaki I, Wada N, Nakano M, et al: Difference in gene expression for matrix metalloproteinase-1 between early and advanced hepatocellular carcinomas. Hepatology 25:580-584, 1997
44. Hayasaka A, Suzuki N, Fujimoto N, et al: Elevated plasma levels of matrix metalloproteinase-9 (92-kd type IV collagenase/gelatinase B) in hepatocellular carcinoma. Hepatology 24:1058-1062, 1996
45. Arii S, Mise M, Harada T, et al: Overexpression of matrix metalloproteinase 9 gene in hepatocellular carcinoma with invasive potential. Hepatology 24:316-322, 1996
46. Tanigawa N, Lu C, Mitsui T, et al: Quantitation of sinusoid-like vessels in hepatocellular carcinoma: Its clinical and prognostic significance. Hepatology 26:1216-1223, 1997
47. Kimura H, Nakajima T, Kagawa K, et al: Angiogenesis in hepatocellular carcinoma as evaluated by CD34 immunohistochemistry. Liver 18:14-19, 1998
48. Hayashi PH, Di Bisceglie AM: The progression of hepatitis B- and C-infections to chronic liver disease and hepatocellular carcinoma: Epidemiology and pathogenesis. Med Clin North Am 89:371-389, 2005
49. Lee WM: Drug-induced hepatotoxicity. N Engl J Med 349:474-485, 2003
50. Elbekai RH, Korashy HM, El-Kadi AO: The effect of liver cirrhosis on the regulation and expression of drug metabolizing enzymes. Curr Drug Metab 5:157-167, 2004
51. Yoshiji H, Kuriyama S, Yoshii J, et al: Vascular endothelial growth factor tightly regulates in vivo development of murine hepatocellular carcinoma cells. Hepatology 28:1489-1496, 1998
52. Shao RX, Otsuka M, Kato N, et al: Acyclic retinoid inhibits human hepatoma cell growth by suppressing fibroblast growth factor-mediated signaling pathways. Gastroenterology 128:86-95, 2005
53. Asada N, Tanaka Y, Hayashido Y, et al: Expression of fibroblast growth factor receptor genes in human hepatoma-derived cell lines. In Vitro Cell Dev Biol Anim 39:321-328, 2003
54. Campbell JS, Hughes SD, Gilbertson DG, et al: Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. Proc Natl Acad Sci U S A 102:3389-3394, 2005
55. Neaud V, Faouzi S, Guirouilh J, et al: Human hepatic myofibroblasts increase invasiveness of hepatocellular carcinoma cells: Evidence for a role of hepatocyte growth factor. Hepatology 26:1458-1466, 1997
56. Neaud V, Faouzi S, Guirouilh J, et al: Hepatocyte growth factor secreted by human liver myofibroblasts increases invasiveness of hepatocellular carcinoma cells. Curr Top Pathol 93:195-203, 1999
57. Fausto N: Growth factors in liver development, regeneration and carcinogenesis. Prog Growth Factor Res 3:219-234, 1991
58. Hisaka T, Yano H, Haramaki M, et al: Expressions of epidermal growth factor family and its receptor in hepatocellular carcinoma cell lines: Relationship to cell proliferation. Int J Oncol 14:453-460, 1999
59. Fausto N, Mead JE, Gruppuso PA, et al: Effects of TGF-betas in the liver: Cell proliferation and fibrogenesis. Ciba Found Symp 157:165-177, 1991
60. Fausto N, Laird AD, Webber EM: Liver regeneration. 2. Role of growth factors and cytokines in hepatic regeneration. Faseb J 9:1527-1536, 1995
61. Castilla A, Prieto J, Fausto N: Transforming growth factors beta 1 and alpha in chronic liver disease. Effects of interferon alfa therapy. N Engl J Med 324:933-940, 1991
62. Derynck R, Goeddel DV, Ullrich A, et al: Synthesis of messenger RNAs for transforming growth factors alpha and beta and the epidermal growth factor receptor by human tumors. Cancer Res 47:707-712, 1987
63. Jhappan C, Stahle C, Harkins RN, et al: TGF alpha overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas. Cell 61:1137-1146, 1990
64. Ito Y, Takeda T, Sakon M, et al: Expression and clinical significance of erb-B receptor family in hepatocellular carcinoma. Br J Cancer 84:1377-1383, 2001
65. Miura H, Miyazaki T, Kuroda M, et al: Increased expression of vascular endothelial growth factor in human hepatocellular carcinoma. J Hepatol 27:854-861, 1997
66. Torimura T, Sata M, Ueno T, et al: Increased expression of vascular endothelial growth factor is associated with tumor progression in hepatocellular carcinoma. Hum Pathol 29:986-991, 1998
67. Poon RT, Ng IO, Lau C, et al: Correlation of serum basic fibroblast growth factor levels with clinicopathologic features and postoperative recurrence in hepatocellular carcinoma. Am J Surg 182:298-304, 2001
68. Suzuki K, Hayashi N, Miyamoto Y, et al: Expression of vascular permeability factor/vascular endothelial growth factor in human hepatocellular carcinoma. Cancer Res 56:3004-3009, 1996
69. Jin-no K, Tanimizu M, Hyodo I, et al: Circulating platelet-derived endothelial cell growth factor increases in hepatocellular carcinoma patients. Cancer 82:1260-1267, 1998
70. Yamaguchi R, Yano H, Iemura A, et al: Expression of vascular endothelial growth factor in human hepatocellular carcinoma. Hepatology 28:68-77, 1998
71. An FQ, Matsuda M, Fujii H, et al: Expression of vascular endothelial growth factor in surgical specimens of hepatocellular carcinoma. J Cancer Res Clin Oncol 126:153-160, 2000
72. Li X, Tang Z, Zhou G: [Expression of vascular endothelial growth factor correlates with invasion and metastasis of hepatocellular carcinoma]. Chung-Hua Chung Liu Tsa Chih [Chinese Journal of Oncology] 20:12-14, 1998
73. Li XM, Tang ZY, Qin LX, et al: Serum vascular endothelial growth factor is a predictor of invasion and metastasis in hepatocellular carcinoma. J Exp Clin Cancer Res 18:511-517, 1999
74. Chow NH, Hsu PI, Lin XZ, et al: Expression of vascular endothelial growth factor in normal liver and hepatocellular carcinoma: An immunohistochemical study. Hum Pathol 28:698-703, 1997
75. Li XM, Tang ZY, Zhou G, et al: Significance of vascular endothelial growth factor mRNA expression in invasion and metastasis of hepatocellular carcinoma. J Exp Clin Cancer Res 17:13-17, 1998
76. Shimoda K, Mori M, Shibuta K, et al: Vascular endothelial growth factor/vascular permeability factor mRNA expression in patients with chronic hepatitis C and hepatocellular carcinoma. Int J Oncol 14:353-359, 1999
77. El-Assal ON, Yamanoi A, Soda Y, et al: Clinical significance of microvessel density and vascular endothelial growth factor expression in hepatocellular carcinoma and surrounding liver: Possible involvement of vascular endothelial growth factor in the angiogenesis of cirrhotic liver. Hepatology 27:1554-1562, 1998
78. Park YN, Kim YB, Yang KM, et al: Increased expression of vascular endothelial growth factor and angiogenesis in the early stage of multistep hepatocarcinogenesis. Arch Pathol Lab Med 124:1061-1065, 2000
79. Matsuo M, Sakurai H, Saiki I: ZD1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor, shows antimetastatic activity using a hepatocellular carcinoma model. Mol Cancer Ther 2:557-561, 2003
80. Philip PA, Mahoney M, Thomas J, et al: Phase II Trial of erlotinib (OSI-774) in patients with hepatocellular or biliary cancer. Presented at 2004 ASCO Annual Meeting Proceedings, New Orleans, LA, June 5-8 2004
81. Thomas MB, Dutta A, Brown T, et al: A Phase II open-label study of OSI-774 (NSC 718781) in Unresectable Hepatocellular Carcinoma. Presented at 2005 American Society of Clinical Oncology Annual Meeting, Orlando, FL, May 14-18, 2005
82. Zhu AX, Sahani D, Norden-Zfoni N, et al: A Phase II Study of gemcitabine, Oxaliplatin in Combination with bevacizumab (GEMOX-B) in patients with Hepatocellular Carcinoma. Presented at 2005 American Society of Clinical Oncology Annual Meeting, Orlando, FL, May 14-18, 2005
83. Schwartz JD, Schwartz M, Leher D, et al: Bevacizumab in hepatocellular carcinoma (HCC) inpatients without metastasis and without invasion of the portal vein. Presented at 2005 American Society of Clinical Oncology Annual Meeting, Orlando, FL, May 14-18, 2005
84. Feng DY, Zheng H, Tan Y, et al: Effect of phosphorylation of MAPK and Stat3 and expression of c-fos and c-jun proteins on hepatocarcinogenesis and their clinical significance. World J Gastroenterol 7:33-36, 2001
85. Schmidt CM, McKillop IH, Cahill PA, et al: Increased MAPK expression and activity in primary human hepatocellular carcinoma. Biochem Biophys Res Commun 236:54-58, 1997
86. McKillop IH, Schmidt CM, Cahill PA, et al: Altered expression of mitogen-activated protein kinases in a rat model of experimental hepatocellular carcinoma. Hepatology 26:1484-1491, 1997
87. Ito Y, Sasaki Y, Horimoto M, et al: Activation of mitogen-activated protein kinases/extracellular signal-regulated kinases in human hepatocellular carcinoma. Hepatology 27:951-958, 1998
88. Toyoda M, Hashimoto N, Tokita K, et al: Increased activity and expression of MAP kinase in HCC model rats induced by 3′-methyl-4-dimethylamino- azobenzene. J Hepatol 31:725-733, 1999
89. Giambartolomei S, Covone F, Levrero M, et al: Sustained activation of the Raf/MEK/Erk pathway in response to EGF in stable cell lines expressing the Hepatitis C Virus (HCV) core protein. Oncogene 20:2606-2610, 2001
90. Tada M, Omata M, Ohto M: Analysis of ras gene mutations in human hepatic malignant tumors by polymerase chain reaction and direct sequencing. Cancer Res 50:1121-1124, 1990
91. Chao HK, Tsai TF, Lin CS, et al: Evidence that mutational activation of the ras genes may not be involved in aflatoxin B(1)-induced human hepatocarcinogenesis, based on sequence analysis of the ras and p53 genes. Mol Carcinog 26:69-73, 1999
92. Boivin-Angele S, Lefrancois L, Froment O, et al: Ras gene mutations in vinyl chloride-induced liver tumours are carcinogen-specific but vary with cell type and species. Int J Cancer 85:223-227, 2000
93. Xia Q, Yi P, Zhan DJ, et al: Liver tumors induced in B6C3F1 mice by 7-chlorobenz[a] anthracene and 7-bromobenz[a]anthracene contain K-ras protooncogene mutations. Cancer Lett 123:21-25, 1998
94. Enomoto T, Weghorst CM, Ward JM, et al: Low frequency of H-ras activation in naturally occurring hepatocellular tumors of C3H/HeNCr mice. Carcinogenesis 14:1939-1944, 1993
95. Wogan GN: Aflatoxins as risk factors for hepatocellular carcinoma in humans. Cancer Res 52:2114s-2118s, 1992
96. Wogan GN: Aflatoxin carcinogenesis: Interspecies potency differences and relevance for human risk assessment. Prog Clin Biol Res 374:123-137, 1992
97. Bos JL: The ras gene family and human carcinogenesis. Mutat Res 195:255-271, 1988
98. Shen HM, Ong CN: Mutations of the p53 tumor suppressor gene and ras oncogenes in aflatoxin hepatocarcinogenesis. Mutat Res 366:23-44, 1996
99. Thelu MA, Zarski JP, Froissant B, et al: C-Ha-ras polymorphism in patients with hepatocellular carcinoma. Comparison of healthy subjects and alcoholic patients with cirrhosis. Gastroenterol Clin Biol 17:903-907, 1993
100. Kato K, Cox AD, Hisaka MM, et al: Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity. Proc Natl Acad Sci U S A 89:6403-6407, 1992
101. Prendergast GC, Rane N: Farnesyltransferase inhibitors: Mechanism and applications. Expert Opin Investig Drugs 10:2105-2116, 2001
102. Richardson KK, Helvering LM, Copple DM, et al: Genetic alterations in the 61st codon of the H-ras oncogene isolated from archival sections of hepatic hyperplasias, adenomas and carcinomas in control groups of B6C3F1 mouse bioassay studies conducted from 1979 to 1986. Carcinogenesis 13:935-941, 1992
103. Baba M, Yamamoto R, Iishi H, et al: Ha-ras mutations in N-nitrosomorpholine-induced lesions and inhibition of hepatocarcinogenesis by antisense sequences in rat liver. Int J Cancer 72:815-820, 1997
104. Pestell KE, Ducruet AP, Wipf P, et al: Small molecule inhibitors of dual specificity protein phosphatases. Oncogene 19:6607-6612, 2000
105. Wang J, Chenivesse X, Henglein B, et al: Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. Nature 343:555-557, 1990
106. Leach FS, Elledge SJ, Sherr CJ, et al: Amplification of cyclin genes in colorectal carcinomas. Cancer Res 53:1986-1989, 1993
107. Weinberg RA: The retinoblastoma protein and cell cycle control. Cell 81:323-330, 1995
108. Ito Y, Matsuura N, Sakon M, et al: Expression and prognostic roles of the G1-S modulators in hepatocellular carcinoma: P27 independently predicts the recurrence. Hepatology 30:90-99, 1999
109. Peng SY, Chou SP, Hsu HC: Association of downregulation of cyclin D1 and of overexpression of cyclin E with p53 mutation, high tumor grade and poor prognosis in hepatocellular carcinoma. J Hepatol 29:281-289, 1998
110. Jung YJ, Lee KH, Choi DW, et al: Reciprocal expressions of cyclin E and cyclih D1 in hepatocellular carcinoma. Cancer Lett 168:57-63, 2001
111. Ito Y, Takeda T, Sakon M, et al: Expression of p57/Kip2 protein in hepatocellular carcinoma. Oncology 61:221-225, 2001
112. Fiorentino M, Altimari A, D'Errico A, et al: Acquired expression of p27 is a favorable prognostic indicator in patients with hepatocellular carcinoma. Clin Cancer Res 6:3966-3972, 2000
113. Ito Y, Takeda T, Sakon M, et al: Expression and prognostic role of cyclin-dependent kinase 1 (cdc2) in hepatocellular carcinoma. Oncology 59:68-74, 2000
114. Nakai S, Masaki T, Shiratori Y, et al: Expression of p57(KIP2) in hepatocellular carcinoma: Relationship between tumor differentiation and patient survival. Int J Oncol 20:769-775, 2002
115. Tannapfel A, Grund D, Katalinic A, et al: Decreased expression of p27 protein is associated with advanced tumor stage in hepatocellular carcinoma. Int J Cancer 89:350-355, 2000
116. Frankel A, Man S, Elliott P, et al: Lack of multicellular drug resistance observed in human ovarian and prostate carcinoma treated with the proteasome inhibitor PS-341. Clin Cancer Res 6:3719-3728, 2000
117. Adams J, Palombella VJ, Elliott PJ: Proteasome inhibition: A new strategy in cancer treatment. Invest New Drugs 18:109-121, 2000
118. Hegewisch-Becker S, Sterneck M, Schubert U, et al: Phase I/II trial of bortezomib in patients with unresectable hepatocellular carcinoma (HCC). Presented at 2004 ASCO Annual Meeting, New Orleans, LA, June 5-8, 2004
119. Roy KK, Sausville EA: Early development of cyclin dependent kinase modulators. Curr Pharm Des 7:1669-1687, 2001
120. Shah M, Kortmansky J, Gone M, et al: Mature results of a phase I study of irinotecan and flavopiridol. Proc Am Soc Clin Oncol 2003 (abstr 1051)
121. Kanai F, Lan KH, Shiratori Y, et al: In vivo gene therapy for alpha-fetoprotein-producing hepatocellular carcinoma by adenovirus-mediated transfer of cytosine deaminase gene. Cancer Res 57:461-465, 1997
122. Ido A, Uto H, Moriuchi A, et al: Gene therapy targeting for hepatocellular carcinoma: Selective and enhanced suicide gene expression regulated by a hypoxia-inducible enhancer linked to a human alpha-fetoprotein promoter. Cancer Res 61:3016-3021, 2001
123. Kanai F, Shiratori Y, Yoshida Y, et al: Gene therapy for alpha-fetoprotein-producing human hepatoma cells by adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene. Hepatology 23:1359-1368, 1996
124. Nemunaitis J, Khuri F, Ganly I, et al: Phase II trial of intratumoral administration of ONYX-015, a replication-selective adenovirus, in patients with refractory head and neck cancer. J Clin Oncol 19:289-298, 2001
125. Nemunaitis J, Ganly I, Khuri F, et al: Selective replication and oncolysis in p53 mutant tumors with ONYX-015, an E1B-55kD gene-deleted adenovirus, in patients with advanced head and neck cancer: A phase II trial. Cancer Res 60:6359-6366, 2000
126. Khuri FR, Nemunaitis J, Ganly I, et al: A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat Med 6:879-885, 2000
127. Masumoto A, Arao S, Otsuki M: Role of betal integrins in adhesion and invasion of hepatocellular carcinoma cells. Hepatology 29:68-74, 1999
128. Koshikawa N, Giannelli G, Cirulli V, et al: Role of cell surface metalloprotease MT1-MMP in epithelial cell migration over laminin-5. J Cell Biol 148:615-624, 2000
129. Carloni V, Mazzocca A, Pantaleo P, et al: The integrin, alpha6beta1, is necessary for the matrix-dependent activation of FAK and MAP kinase and the migration of human hepatocarcinoma cells. Hepatology 34:42-49, 2001
130. Carloni V, Romanelli RG, Mercurio AM, et al: Knockout of alpha6 beta1-integrin expression reverses the transformed phenotype of hepatocarcinoma cells. Gastroenterology 115:433-442, 1998
131. Torimura T, Ueno T, Kin M, et al: Coordinated expression of integrin alpha6beta1 and laminin in hepatocellular carcinoma. Hum Pathol 28:1131-1138, 1997
132. Torimura T, Ueno T, Kin M, et al: Integrin alpha6beta1 plays a significant role in the attachment of hepatoma cells to laminin. J Hepatol 31:734-740, 1999
133. Yao M, Zhou XD, Zha XL, et al: Expression of the integrin alpha5 subunit and its mediated cell adhesion in hepatocellular carcinoma. J Cancer Res Clin Oncol 123:435-440, 1997
134. Ozaki I, Yamamoto K, Mizuta T, et al: Differential expression of laminin receptors in human hepatocellular carcinoma. Gut 43:837-842, 1998
135. Yamamoto H, Itoh F, Sakamoto H, et al: Association of reduced cell adhesion regulator messenger RNA expression with tumor progression in human hepatocellular carcinoma. Int J Cancer 74:251-254, 1997
136. Harada T, Arii S, Mise M, et al: Membrane-type matrix metalloproteinase-1(MT1-MTP) gene is overexpressed in highly invasive hepatocellular carcinomas. J Hepatol 28:231-239, 1998
137. Kleiner DE, Stetler-Stevenson WG: Matrix metalloproteinases and metastasis. Cancer Chemother Pharmacol 43 Suppl:S42-S51, 1999
138. Musso O, Theret N, Campion JP, et al: In situ detection of matrix metalloproteinase-2 (MMP2) and the metalloproteinase inhibitor TIMP2 transcripts in human primary hepatocellular carcinoma and in liver metastasis. J Hepatol 26:593-605, 1997
139. Monvoisin A, Bisson C, Si-Tayeb K, et al: Involvement of matrix metalloproteinase type-3 in hepatocyte growth factor-induced invasion of human hepatocellular carcinoma cells. Int J Cancer 97:157-162, 2002
140. Zucker S, Eckhardt SG, Rowinsky EK: Plasma MMPs as surrogates of BAY 12-9566. J Clin Oncol 18:1805-1806, 2000
141. Shiota G, Okubo M, Noumi T, et al: Cyclooxygenase-2 expression in hepatocellular carcinoma. Hepatogastroenterology 46:407-412, 1999
142. Kondo M, Yamamoto H, Nagano H, et al: Increased expression of COX-2 in nontumor liver tissue is associated with shorter disease-free survival in patients with hepatocellular carcinoma. Clin Cancer Res 5:4005-4012, 1999
143. Bae SH, Jung ES, Park YM, et al: Expression of cyclooxygenase-2 (COX-2) in hepatocellular carcinoma and growth inhibition of hepatoma cell lines by a COX-2 inhibitor, NS-398. Clin Cancer Res 7:1410-1418, 2001
144. Cheng AS, Chan HL, Leung WK, et al: Specific COX-2 inhibitor, NS-398, suppresses cellular proliferation and induces apoptosis in human hepatocellular carcinoma cells. Int J Oncol 23:113-119, 2003
145. Rahman MA, Dhar DK, Masunaga R, et al: Sulindac and exisulind exhibit a significant antiproliferative effect and induce apoptosis in human hepatocellular carcinoma cell lines. Cancer Res 60:2085-2089, 2000
146. Nakae D, Yoshiji H, Mizumoto Y, et al: High incidence of hepatocellular carcinomas induced by a choline deficient L-amino acid defined diet in rats. Cancer Res 52:5042-5045, 1992
147. Denda A, Endoh T, Tang Q, et al: Prevention by inhibitors of arachidonic acid cascade of liver carcinogenesis, cirrhosis and oxidative DNA damage caused by a choline-deficient, L-amino acid-defined diet in rats. Mutat Res 402:279-288, 1998
148. Sano K, Takayama T, Murakami K, et al: Overexpression of retinoic acid receptor alpha in hepatocellular carcinoma. Clin Cancer Res 9:3679-3683, 2003
149. Sporn MB: Carcinogenesis and cancer: Different perspectives on the same disease. Cancer Res 51:6215-6218, 1991
150. Sporn MB, Roberts AB: Role of retinoids in differentiation and carcinogenesis. Cancer Res 43:3034-3040, 1983
151. nd ed. New York, Raven Press, 1994
152. Boone CW, Kelloff GJ, Malone WE: Identification of candidate cancer chemopreventive agents and their evaluation in animal models and human clinical trials: A review. Cancer Res 50:2-9, 1990
153. Lippman SM: Head and neck chemoprevention: Recent advances. Cancer Control 4:128-135, 1997
154. Lotan R: Retinoids in cancer chemoprevention. Faseb J 10:1031-1039, 1996
155. Lotan R: Retinoids and chemoprevention of aerodigestive tract cancers. Cancer Metastasis Rev 16:349-356, 1997
156. Geubel AP, De Galocsy C, Alves N, et al: Liver damage caused by therapeutic vitamin A administration: Estimate of dose-related toxicity in 41 cases. Qastroenterology 100:1701-1709, 1991
157. Muto Y, Moriwaki H, Shiratori Y: Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Digestion 59 Suppl 289-91, 1998
158. Kim DG, Jo BH, You KR, et al: Apoptosis induced by retinoic acid in Hep 3B cells in vitro. Cancer Lett 107:149-159, 1996
159. Newsome PN, Beldon I, Moussa Y, et al: Low serum retinol levels are associated with hepatocellular carcinoma in patients with chronic liver disease. Aliment Pharmacol Ther 14:1295-1301, 2000
160. Muto Y, Moriwaki H, Ninomiya M, et al: Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. N Engl J Med 334:1561-1567, 1996
161. Obora A, Shiratori Y, Okuno M, et al: Synergistic induction of apoptosis by acyclic retinoid and interferon-beta in human hepatocellular carcinoma cells. Hepatology 36:1115-1124, 2002
162. Furuse J: Personal Communication, in Head DoHPODoMONCCHe (ed). Chiba, Japan, 2005
163. Meyskens FL Jr, Jacobson J, Nguyen B, et al: Phase II trial of oral beta-all trans-retinoic acid in hepatocellular carcinoma (SWOG 9157). Invest New Drugs 16:171-173, 1998
164. Hsu C, Huang CL, Hsu HC, et al: HER-2/neu overexpression is rare in hepatocellular carcinoma and not predictive of anti-HER-2/neu regulation of cell growth and chemosensitivity. Cancer 94:415-420, 2002
165. Prange W, Schirmacher P: Absence of therapeutically relevant c-erbB-2 expression in human hepatocellular carcinomas. Oncol Rep 8:727-730, 2001
166. Inui Y, Higashiyama S, Kawata S, et al: Expression of heparin-binding epidermal growth factor in human hepatocellular carcinoma. Gastroenterology 107:1799-1804, 1994
167. Morimitsu Y, Hsia CC, Kojiro M, et al: Nodules of less-differentiated tumor within or adjacent to hepatocellular carcinoma: Relative expression of transforming growth factor-alpha and its receptor in the different areas of tumor. Hum Pathol 26:1126-1132, 1995
168. Kiss A, Wang NJ, Xie JP, et al: Analysis of transforming growth factor (TGF)-alpha/epidermal growth factor receptor, hepatocyte growth Factor/c-met, TGF-beta receptor type II, and p53 expression in human hepatocellular carcinomas. Clin Cancer Res 3:1059-1066, 1997
169. Mise M, Arii S, Higashituji H, et al: Clinical significance of vascular endothelial growth factor and basic fibroblast growth factor gene expression in liver tumor. Hepatology 23:455-464, 1996
170. Su Q, Liu Y: [Expression of c-erbB-2 protein and EGF receptor in hepatitis B, cirrhosis and hepatocellular carcinoma]. Zhonghua Bing Li Xue Za Zhi 24:93-95, 1995
171. Baselga J: Combining the anti-EGFR agent gefitinib with chemotherapy in non-small-cell lung cancer: How do we go from INTACT to impact? J Clin Oncol 22:759-761, 2004
172. Blackledge G, Averbuch S: Gefitinib ('Iressa', ZD1839) and new epidermal growth factor receptor inhibitors. Br J Cancer 90:566-572, 2004
173. Two new drugs for colon cancer. Med Lett Drugs Ther 46:46-48, 2004
174. Khalil MY, Grandis JR, Shin DM: Targeting epidermal growth factor receptor: Novel therapeutics in the management of cancer. Expert Rev Anticancer Ther 3:367-380, 2003
175. Zips D, Krause M, Hessel F, et al: Experimental study on different combination schedules of VEGF-receptor inhibitor PTK787/ZK222584 and fractionated irradiation. Anticancer Res 23:3869-3876, 2003
176. Schoenberger J, Grimm D, Kossmehl P, et al: Effects of PTK787/ZK222584, a tyrosine kinase inhibitor, on the growth of a poorly differentiated thyroid carcinoma: An animal study. Endocrinology 145:1031-1038, 2004
177. Traxler P, Allegrini PR, Brandt R, et al: AEE788: a dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res 64:4931-4941, 2004
178. Sebolt-Leopold JS, Dudley DT, Herrera R, et al: Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med 5:810-816, 1999
179. Adjei AA: Blocking oncogenic Ras signaling for cancer therapy. J Natl Cancer Inst 93:1062-1074, 2001
180. Haller DG: Future directions in the treatment of pancreatic cancer. Semin Oncol 29:31-39, 2002
181. Nagase T, Kawata S, Tamura S, et al: Manumycin and gliotoxin derivative KT7595 block Ras farnesylation and cell growth but do not disturb lamin farnesylation and localization in human tumour cells. Br J Cancer 76:1001-1010, 1997
182. Nemunaitis J, Holmlund JT, Kraynak M, et al: Phase I evaluation of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase C-alpha, in patients with advanced cancer. J Clin Oncol 17:3586-3595, 1999
183. Kambe H, Kishima Y, Kuroda T, et al: Protein kinase C inhibitor, H-7 suppresses the growth activity of hepatoma-derived growth factor. Hepatogastroenterology 47:1645-1648, 2000
184. Okamoto Y, Nishimura K, Nakayama M, et al: Protein kinase C in the regenerating rat liver. Biochem Biophys Res Commun 151:1144-1149, 1988
185. Perletti GP, Smeraldi C, Porro D, et al: Involvement of the alpha isoenzyme of protein kinase C in the growth inhibition induced by phorbol esters in MH1C1 hepatoma cells. Biochem Biophys Res Commun 205:1589-1594, 1994
186. Bae SK, Baek JH, Lee YM, et al: Hypoxia-induced apoptosis in human hepatocellular carcinoma cells: A possible involvement of the 6-TG-sensitive protein kinase(s)-dependent signaling pathway. Cancer Lett 126:97-104, 1998
187. Ducher L, Croquet F, Gil S, et al: Differential expression of five
188. Chang KJ, Lin JK, Lee PH, et al: The altered activity of membrane-bound protein kinase C in human liver cancer. Cancer Lett 105:211-215, 1996
189. Weihrauch M, Benicke M, Lehnen G, et al: Frequent k- ras -2 mutations and p16(INK4A) methylation in hepatocellular carcinomas in workers exposed to vinyl chloride. Br J Cancer 84:982-989, 2001
190. Akinaga S, Gomi K, Morimoto M, et al: Antitumor activity of UCN-01, a selective inhibitor of protein kinase C, in murine and human tumor models. Cancer Res 51:4888-4892, 1991
191. Swannie HC, Kaye SB: Protein kinase C inhibitors. Curr Oncol Rep 4:37-46, 2002
192. Azechi H, Nishida N, Fukuda Y, et al: Disruption of the p16/cyclin D1/retinoblastoma protein pathway in the majority of human hepatocellular carcinomas. Oncology 60:346-354, 2001
193. Ito Y, Matsuura N, Sakon M, et al: Both cell proliferation and apoptosis significantly predict shortened disease-free survival in hepatocellular carcinoma. Br J Cancer 81:747-751, 1999
194. Tan AR, Swain SM: Review of flavopiridol, a cyclin-dependent kinase inhibitor, as breast cancer therapy. Semin Oncol 29:77-85, 2002
195. Zhai S, Senderowicz AM, Sausville EA, et al: Flavopiridol, a novel cyciin-dependent kinase inhibitor, in clinical development. Ann Pharmacother 36:905-911, 2002
196. Senderowicz AM: Flavopiridol: The first cyclin-dependent kinase inhibitor in human clinical trials. Invest New Drugs 17:313-320, 1999
197. Kerr JS, Wexlr RS, Mousa SA, et al: Novel small molecule alpha v integrin antagonists: Comparative anti-cancer efficacy with known angiogenesis inhibitors. Anticancer Res 19:959-968, 1999
198. Senderowicz AM: Small molecule modulators of cyclin-dependent kinases for cancer therapy. Oncogene 19:6600-6606, 2000
199. Senderowicz AM, Sausville EA: RESPONSE: Re: Preclinical and clinical development of cyclin-dependent kinase modulators. J Natl Cancer Inst 92:1185, 2000
200. Senderowicz AM, Sausville EA: Preclinical and clinical development of cyclin-dependent kinase modulators. J Natl Cancer Inst 92:376-387, 2000
201. Hidalgo M, Rowinsky EK: The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene 19:6680-6686, 2000
202. Hatake K, Mishima Y, Terui Y: (Proteasome inhibitors]. Gan To Kagaku Ryoho31:999-1002, 2004
203. Richardson PG, Hideshima T, Mitsiades C, et ai: Proteasome inhibition in hematologic malignancies. Ann Med 36:304-314, 2004
204. Park DJ, Lenz HJ: The role of proteasome inhibitors in solid tumors. Ann Med 36:296-303, 2004
205. Capriotti T: New oncology strategy: Molecular targeting of cancer cells. Medsurg Nurs 13:191-195, 2004