Medical Molecular Morphology

, Volume 44, Issue 4, pp 183–189 | Cite as

Sorafenib: complexities of Raf-dependent and Raf-independent signaling are now unveiled

Review

Abstract

Hepatocellular carcinoma (HCC) is the most common primary cancer worldwide. The only current drug available for clinical treatment of HCC is sorafenib, which inhibits multiple signaling kinases including Raf family members, platelet-derived growth factor receptor, vascular endothelial growth factor receptors 1 and 2, c-Kit, and Fms-like tyrosine kinase 3. Many studies have revealed that the mechanism underlying the antitumor effect of sorafenib is complex. Because sorafenib inhibits C-Raf more potently than B-Raf, the therapeutic efficacy of sorafenib is strongly influenced by the relative expression and activity of B-Raf and C-Raf and the complex interactions between these factors. Moreover, Rafindependent signaling mechanisms have recently emerged as important pathways of sorafenib-induced cell death. Basic research studies have suggested that using sorafenib as part of a combination therapy may improve its effect, although this has yet to be confirmed by clinical evidence. Further studies of the functional mechanism of sorafenib are required to advance the development of targeted therapy for HCC. To aid future work on sorafenib, we here review the current literature pertaining to sorafenib signaling and its clinical efficacy in both monotherapy and combination therapy.

Keywords

Hepatocellular carcinoma Sorafenib Raf Myeloid cell leukemia-1 Endoplasmic reticulum stress 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Llovet JM, Burroughs A, Bruix J (2003) Hepatocellular carcinoma. Lancet 362:1907–1917PubMedCrossRefGoogle Scholar
  2. 2.
    Llovet JM, Bruix J (2003) Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 37:429–442PubMedCrossRefGoogle Scholar
  3. 3.
    Bruix J, Sherman M (2005) Management of hepatocellular carcinoma. Hepatology 42:1208–1236PubMedCrossRefGoogle Scholar
  4. 4.
    Sherman M (2008) Recurrence of hepatocellular carcinoma. N Engl J Med 359:2045–2047PubMedCrossRefGoogle Scholar
  5. 5.
    Ishikawa Y, Wada I, Fukumoto M (2001) Alpha-particle carcinogenesis in Thorotrast patients: epidemiology, dosimetry, pathology, and molecular analysis. J Environ Pathol Toxicol Oncol 20: 311–315PubMedGoogle Scholar
  6. 6.
    El Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132:2557–2576PubMedCrossRefGoogle Scholar
  7. 7.
    Starley BQ, Calcagno CJ, Harrison SA (2010) Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 51:1820–1832PubMedCrossRefGoogle Scholar
  8. 8.
    Gollob JA, Wilhelm S, Carter C, Kelley SL (2006) Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol 33:392–406PubMedCrossRefGoogle Scholar
  9. 9.
    Kolch W, Kotwaliwale A, Vass K, Janosch P (2002) The role of Raf kinases in malignant transformation. Expert Rev Mol Med 4:1–18PubMedCrossRefGoogle Scholar
  10. 10.
    Roberts PJ, Der CJ (2007) Targeting the Raf-MEK-ERK mitogenactivated protein kinase cascade for the treatment of cancer. Oncogene 26:3291–3310PubMedCrossRefGoogle Scholar
  11. 11.
    Yu C, Bruzek LM, Meng XW, Gores GJ, Carter CA, Kaufmann SH, Adjei AA (2005) The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006. Oncogene 24:6861–6869PubMedCrossRefGoogle Scholar
  12. 12.
    Rahmani M, Davis EM, Bauer C, Dent P, Grant S (2005) Apoptosis induced by the kinase inhibitor BAY 43-9006 in human leukemia cells involves down-regulation of Mcl-1 through inhibition of translation. J Biol Chem 280:35217–35227PubMedCrossRefGoogle Scholar
  13. 13.
    Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390PubMedCrossRefGoogle Scholar
  14. 14.
    Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z (2009) Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 10:25–34PubMedCrossRefGoogle Scholar
  15. 15.
    Pinter M, Sieghart W, Graziadei I, Vogel W, Maieron A, Königsberg R, Weissmann A, Kornek G, Plank C, Peck-Radosavljevic M (2009) Sorafenib in unresectable hepatocellular carcinoma from mild to advanced stage liver cirrhosis. Oncologist 14:70–76PubMedCrossRefGoogle Scholar
  16. 16.
    Schütte K, Zimmermann L, Bornschein J, Csepregi A, Rühl R, Ricke J, Malfertheiner P (2011) Sorafenib therapy in patients with advanced hepatocellular carcinoma in advanced liver cirrhosis. Digestion 83:275–282PubMedCrossRefGoogle Scholar
  17. 17.
    Karreth FA, DeNicola GM, Winter SP, Tuveson DA (2009) C-Raf inhibits MAPK activation and transformation by B-Raf(V600E). Mol Cell 36:477–486PubMedCrossRefGoogle Scholar
  18. 18.
    Siegel AB, Olsen SK, Magun A, Brown RS Jr (2010) Sorafenib: where do we go from here? Hepatology 52:360–369PubMedCrossRefGoogle Scholar
  19. 19.
    Cox AD, Der CJ (2010) The raf inhibitor paradox: unexpected consequences of targeted drugs. Cancer Cell 17:221–223PubMedCrossRefGoogle Scholar
  20. 20.
    Wellbrock C, Karasarides M, Marais R (2004) The RAF proteins take centre stage. Nat Rev Mol Cell Biol 5:875–885PubMedCrossRefGoogle Scholar
  21. 21.
    Garnett MJ, Rana S, Paterson H, Barford D, Marais R (2005) Wildtype and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Mol Cell 20:963–969PubMedCrossRefGoogle Scholar
  22. 22.
    Rushworth LK, Hindley AD, O’Neill E, Kolch W (2006) Regulation and role of Raf-1/B-Raf heterodimerization. Mol Cell Biol 26:2262–2272PubMedCrossRefGoogle Scholar
  23. 23.
    Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D, Marais R (2004) Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116:855–867PubMedCrossRefGoogle Scholar
  24. 24.
    Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64:7099–7109PubMedCrossRefGoogle Scholar
  25. 25.
    Noble C, Mercer K, Hussain J, Carragher L, Giblett S, Hayward R, Patterson C, Marais R, Pritchard CA (2008) CRAF autophosphorylation of serine 621 is required to prevent its proteasome-mediated degradation. Mol Cell 31:862–872PubMedCrossRefGoogle Scholar
  26. 26.
    Zang M, Gong J, Luo L, Zhou J, Xiang X, Huang W, Huang Q, Luo X, Olbrot M, Peng Y, Chen C, Luo Z (2008) Characterization of Ser338 phosphorylation for Raf-1 activation. J Biol Chem 283:31429–31437PubMedCrossRefGoogle Scholar
  27. 27.
    Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, Hussain J, Reis-Filho JS, Springer CJ, Pritchard C, Marais R (2010) Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140:209–221PubMedCrossRefGoogle Scholar
  28. 28.
    Shim JH, Park JW, Choi JI, Park BJ, Kim CM (2009) Practical efficacy of sorafenib monotherapy for advanced hepatocellular carcinoma patients in a hepatitis B virus-endemic area. J Cancer Res Clin Oncol 135:617–625PubMedCrossRefGoogle Scholar
  29. 29.
    Ogasawara S, Kanai F, Obi S, Sato S, Yamaguchi T, Azemoto R, Mizumoto H, Koushima Y, Morimoto N, Hirata N, Toriyabe T, Shinozaki Y, Ooka Y, Mikata R, Chiba T, Okabe S, Imazeki F, Yoshikawa M, Yokosuka O (2011) Safety and tolerance of sorafenib in Japanese patients with advanced hepatocellular carcinoma. Hepatol Int 5:850–856PubMedCrossRefGoogle Scholar
  30. 30.
    Tannapfel A, Sommerer F, Benicke M, Katalinic A, Uhlmann D, Witzigmann H, Hauss J, Wittekind C (2003) Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut 52:706–712PubMedCrossRefGoogle Scholar
  31. 31.
    Newell P, Toffanin S, Villanueva A, Chiang DY, Minguez B, Cabellos L, Savic R, Hoshida Y, Lim KH, Melgar-Lesmes P, Yea S, Peix J, Deniz K, Fiel MI, Thung S, Alsinet C, Tovar V, Mazzaferro V, Bruix J, Roayaie S, Schwartz M, Friedman SL, Llovet JM (2009) Ras pathway activation in hepatocellular carcinoma and anti-tumoral effect of combined sorafenib and rapamycin in vivo. J Hepatol 51:725–733PubMedCrossRefGoogle Scholar
  32. 32.
    Ashkenazi A (2008) Directing cancer cells to self-destruct with proapoptotic receptor agonists. Nat Rev Drug Discov 7:1001–1012PubMedCrossRefGoogle Scholar
  33. 33.
    Leber B, Geng F, Kale J, Andrews DW (2010) Drugs targeting Bcl-2 family members as an emerging strategy in cancer. Expert Rev Mol Med 12:e28PubMedCrossRefGoogle Scholar
  34. 34.
    Akgul C (2009) Mcl-1 is a potential therapeutic target in multiple types of cancer. Cell Mol Life Sci 66:1326–1336PubMedCrossRefGoogle Scholar
  35. 35.
    Thomas LW, Lam C, Edwards SW (2010) Mcl-1; the molecular regulation of protein function. FEBS Lett 584:2981–2989PubMedCrossRefGoogle Scholar
  36. 36.
    Ulivi P, Arienti C, Amadori D, Fabbri F, Carloni S, Tesei A, Vannini I, Silvestrini R, Zoli W (2009) Role of RAF/MEK/ERK pathway, p-STAT-3 and Mcl-1 in sorafenib activity in human pancreatic cancer cell lines. J Cell Physiol 220:214–221PubMedCrossRefGoogle Scholar
  37. 37.
    Rahmani M, Davis EM, Crabtree TR, Habibi JR, Nguyen TK, Dent P, Grant S (2007) The kinase inhibitor sorafenib induces cell death through a process involving induction of endoplasmic reticulum stress. Mol Cell Biol 27:5499–5513PubMedCrossRefGoogle Scholar
  38. 38.
    Tsukada M, Oshumi Y (1993) Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett 333:169–174PubMedCrossRefGoogle Scholar
  39. 39.
    Kim I, Xu W, Reed JC (2008) Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov 7:1013–1030PubMedCrossRefGoogle Scholar
  40. 40.
    McConkey DJ, Zhu K (2008) Mechanisms of proteasome inhibitor action and resistance in cancer. Drug Resist Updat 11:164–179PubMedCrossRefGoogle Scholar
  41. 41.
    Schleicher SM, Moretti L, Varki V, Lu B (2010) Progress in the unraveling of the endoplasmic reticulum stress/autophagy pathway and cancer: implications for future therapeutic approaches. Drug Resist Updat 13:79–86PubMedCrossRefGoogle Scholar
  42. 42.
    Park MA, Zhang G, Martin AP, Hamed H, Mitchell C, Hylemon PB, Graf M, Rahmani M, Ryan K, Liu X, Spiegel S, Norris J, Fisher PB, Grant S, Dent P (2008) Vorinostat and sorafenib increase ER stress, autophagy and apoptosis via ceramide-dependent CD95 and PERK activation. Cancer Biol Ther 7:1648–1662PubMedCrossRefGoogle Scholar
  43. 43.
    Niessner H, Beck D, Sinnberg T, Lasithiotakis K, Maczey E, Gogel J, Venturelli S, Berger A, Mauthe M, Toulany M, Flaherty K, Schaller M, Schadendorf D, Proikas-Cezanne T, Schittek B, Garbe C, Kulms D, Meier F (2011) The farnesyl transferase inhibitor lonafarnib inhibits mTOR signaling and enforces sorafenibinduced apoptosis in melanoma cells. J Invest Dermatol 131:468–479PubMedCrossRefGoogle Scholar
  44. 44.
    Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M, Carter C (2006) Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 66:11851–11858PubMedCrossRefGoogle Scholar
  45. 45.
    Pignochino Y, Grignani G, Cavalloni G, Motta M, Tapparo M, Bruno S, Bottos A, Gammaitoni L, Migliardi G, Camussi G, Alberghini M, Torchio B, Ferrari S, Bussolino F, Fagioli F, Picci P, Aglietta M (2009) Sorafenib blocks tumour growth, angiogenesis and metastatic potential in preclinical models of osteosarcoma through a mechanism potentially involving the inhibition of ERK1/2, MCL-1 and ezrin pathways. Mol Cancer 8:118PubMedCrossRefGoogle Scholar
  46. 46.
    Ramakrishnan V, Timm M, Haug JL, Kimlinger TK, Wellik LE, Witzig TE, Rajkumar SV, Adjei AA, Kumar S (2010) Sorafenib, a dual Raf kinase/vascular endothelial growth factor receptor inhibitor has significant anti-myeloma activity and synergizes with common anti-myeloma drugs. Oncogene 29:1190–1202PubMedCrossRefGoogle Scholar
  47. 47.
    Peck-Radosavljevic M, Greten TF, Lammer J, Rosmorduc O, Sangro B, Santoro A, Bolondi L (2010) Consensus on the current use of sorafenib for the treatment of hepatocellular carcinoma. Eur J Gastroenterol Hepatol 22:391–398PubMedCrossRefGoogle Scholar
  48. 48.
    Shen YC, Hsu C, Cheng AL (2010) Molecular targeted therapy for advanced hepatocellular carcinoma: current status and future perspectives. J Gastroenterol 45:794–807PubMedCrossRefGoogle Scholar
  49. 49.
    Kudo M, Ueshima K (2010) Positioning of a molecular-targeted agent, sorafenib, in the treatment algorithm for hepatocellular carcinoma and implication of many complete remission cases in Japan. Oncology 78(suppl 1):154–166PubMedCrossRefGoogle Scholar
  50. 50.
    Meng XW, Lee SH, Dai H, Loegering D, Yu C, Flatten K, Schneider P, Dai NT, Kumar SK, Smith BD, Karp JE, Adjei AA, Kaufmann SH (2007) Mcl-1 as a buffer for proapoptotic Bcl-2 family members during TRAIL-induced apoptosis: a mechanistic basis for sorafenib (Bay 43-9006)-induced TRAIL sensitization. J Biol Chem 282:29831–29846PubMedCrossRefGoogle Scholar
  51. 51.
    Rosato RR, Almenara JA, Coe S, Grant S (2007) The multikinase inhibitor sorafenib potentiates TRAIL lethality in human leukemia cells in association with Mcl-1 and cFLIPL down-regulation. Cancer Res 67:9490–9500PubMedCrossRefGoogle Scholar
  52. 52.
    Ricci MS, Kim SH, Ogi K, Plastaras JP, Ling J, Wang W, Jin Z, Liu YY, Dicker DT, Chiao PJ, Flaherty KT, Smith CD, El-Deiry WS (2007) Reduction of TRAIL-induced Mcl-1 and cIAP2 by c-Myc or sorafenib sensitizes resistant human cancer cells to TRAIL-induced death. Cancer Cell 12:66–80PubMedCrossRefGoogle Scholar
  53. 53.
    Dasmahapatra G, Yerram N, Dai Y, Dent P, Grant S (2007) Synergistic interactions between vorinostat and sorafenib in chronic myelogenous leukemia cells involve Mcl-1 and p21CIP1 downregulation. Clin Cancer Res 13:4280–4290PubMedCrossRefGoogle Scholar
  54. 54.
    Lin X, Morgan-Lappe S, Huang X, Li L, Zakula DM, Vernetti LA, Fesik SW, Shen Y (2007) “Seed” analysis of off-target siRNAs reveals an essential role of Mcl-1 in resistance to the small-molecule Bcl-2/Bcl-XL inhibitor ABT-737. Oncogene 26:3972–3979PubMedCrossRefGoogle Scholar
  55. 55.
    Rausch V, Liu L, Kallifatidis G, Baumann B, Mattern J, Gladkich J, Wirth T, Schemmer P, Büchler MW, Zöller M, Salnikov AV, Herr I (2010) Synergistic activity of sorafenib and sulforaphane abolishes pancreatic cancer stem cell characteristics. Cancer Res 70:5004–5013PubMedCrossRefGoogle Scholar
  56. 56.
    Wei G, Wang M, Carr BI (2010) Sorafenib combined vitamin K induces apoptosis in human pancreatic cancer cell lines through RAF/MEK/ERK and c-Jun NH2-terminal kinase pathways. J Cell Physiol 224:112–119PubMedGoogle Scholar
  57. 57.
    Wei G, Wang M, Hyslop T, Wang Z, Carr BI (2010) Vitamin K enhancement of sorafenib-mediated HCC cell growth inhibition in vitro and in vivo. Int J Cancer 127:2949–2958PubMedCrossRefGoogle Scholar
  58. 58.
    Zhang W, Zhu XD, Sun HC, Xiong YQ, Zhuang PY, Xu HX, Kong LQ, Wang L, Wu WZ, Tang ZY (2010) Depletion of tumor-associated macrophages enhances the effect of sorafenib in metastatic liver cancer models by antimetastatic and antiangiogenic effects. Clin Cancer Res 16:3420–3430PubMedCrossRefGoogle Scholar
  59. 59.
    Finn RS (2010) Development of molecularly targeted therapies in hepatocellular carcinoma: where do we go now? Clin Cancer Res 16:390–397PubMedCrossRefGoogle Scholar
  60. 60.
    Treiber G (2009) mTOR inhibitors for hepatocellular cancer: a forward-moving target. Expert Rev Anticancer Ther 9:247–261PubMedCrossRefGoogle Scholar
  61. 61.
    Blumberg BS, Larouzé B, London WT, Werner B, Hesser JE, Millman I, Saimot G, Payet M (1975) The relation of infection with the hepatitis B agent to primary hepatic carcinoma. Am J Pathol 81:669–682PubMedGoogle Scholar
  62. 62.
    Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M (1989) Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244:359–362PubMedCrossRefGoogle Scholar
  63. 63.
    Himmelsbach K, Sauter D, Baumert TF, Ludwig L, Blum HE, Hildt E (2009) New aspects of an anti-tumour drug: sorafenib efficiently inhibits HCV replication. Gut 58:1644–1653PubMedCrossRefGoogle Scholar
  64. 64.
    Wang Z, Zhou J, Fan J, Qiu SJ, Yu Y, Huang XW, Tang ZY (2008) Effect of rapamycin alone and in combination with sorafenib in an orthotopic model of human hepatocellular carcinoma. Clin Cancer Res 14:5124–5130PubMedCrossRefGoogle Scholar
  65. 65.
    Ou DL, Shen YC, Liang JD, Liou JY, Yu SL, Fan HH, Wang DS, Lu YS, Hsu C, Cheng AL (2009) Induction of Bim expression contributes to the antitumor synergy between sorafenib and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor CI-1040 in hepatocellular carcinoma. Clin Cancer Res 15:5820–5828PubMedCrossRefGoogle Scholar
  66. 66.
    Huynh H, Ngo VC, Koong HN, Poon D, Choo SP, Toh HC, Thng CH, Chow P, Ong HS, Chung A, Goh BC, Smith PD, Soo KC (2010) AZD6244 enhances the anti-tumor activity of sorafenib in ectopic and orthotopic models of human hepatocellular carcinoma (HCC). J Hepatol 52:79–87PubMedCrossRefGoogle Scholar
  67. 67.
    Chen KF, Yu HC, Liu TH, Lee SS, Chen PJ, Cheng AL (2010) Synergistic interactions between sorafenib and bortezomib in hepatocellular carcinoma involve PP2A-dependent Akt inactivation. J Hepatol 52:88–95PubMedCrossRefGoogle Scholar
  68. 68.
    Martinelli E, Troiani T, Morgillo F, Rodolico G, Vitagliano D, Morelli MP, Tuccillo C, Vecchione L, Capasso A, Orditura M, De Vita F, Eckhardt SG, Santoro M, Berrino L, Ciardiello F (2010) Synergistic antitumor activity of sorafenib in combination with epidermal growth factor receptor inhibitors in colorectal and lung cancer cells. Clin Cancer Res 16:4990–5001PubMedCrossRefGoogle Scholar
  69. 69.
    Hikita H, Takehara T, Shimizu S, Kodama T, Shigekawa M, Iwase K, Hosui A, Miyagi T, Tatsumi T, Ishida H, Li W, Kanto T, Hiramatsu N, Hayashi N (2010) The Bcl-xL inhibitor, ABT-737, efficiently induces apoptosis and suppresses growth of hepatoma cells in combination with sorafenib. Hepatology 52:1310–1321PubMedCrossRefGoogle Scholar
  70. 70.
    Gedaly R, Angulo P, Hundley J, Daily MF, Chen C, Koch A, Evers BM (2010) PI-103 and sorafenib inhibit hepatocellular carcinoma cell proliferation by blocking Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. Anticancer Res 30:4951–4958PubMedGoogle Scholar
  71. 71.
    Prete SD, Montella L, Caraglia M, Maiorino L, Cennamo G, Montesarchio V, Piai G, Febbraro A, Tarantino L, Capasso E, Palmieri G, Guarrasi R, Bianco M, Mamone R, Savastano C, Pisano A, Vincenzi B, Sabia A, D’Agostino A, Faiola V, Addeo R (2010) Sorafenib plus octreotide is an effective and safe treatment in advanced hepatocellular carcinoma: multicenter phase II So.LAR. study. Cancer Chemother Pharmacol 66:837–844CrossRefGoogle Scholar
  72. 72.
    Zhao JD, Liu J, Ren ZG, Gu K, Zhou ZH, Li WT, Chen Z, Xu ZY, Liu LM, Jiang GL (2010) Maintenance of Sorafenib following combined therapy of three-dimensional conformal radiation therapy/intensity-modulated radiation therapy and transcatheter arterial chemoembolization in patients with locally advanced hepatocellular carcinoma: a phase I/II study. Radiat Oncol 5:12PubMedCrossRefGoogle Scholar
  73. 73.
    Abou-Alfa GK, Johnson P, Knox JJ, Capanu M, Davidenko I, Lacava J, Leung T, Gansukh B, Saltz LB (2010) Doxorubicin plus sorafenib vs. doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA 304:2154–2160PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society for Clinical Molecular Morphology 2011

Authors and Affiliations

  1. 1.Department of Medical TechnologyNiigata University Graduate School of Health SciencesNiigataJapan
  2. 2.Department of Pathology, Institute of Development, Aging and CancerTohoku UniversitySendaiJapan

Personalised recommendations