{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T08:02:09Z","timestamp":1791014529327,"version":"4.1.0"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2010,8,6]],"date-time":"2010-08-06T00:00:00Z","timestamp":1281052800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2010,8,6]],"date-time":"2010-08-06T00:00:00Z","timestamp":1281052800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cancer Gene Ther"],"published-print":{"date-parts":[[2010,12]]},"DOI":"10.1038\/cgt.2010.40","type":"journal-article","created":{"date-parts":[[2010,8,6]],"date-time":"2010-08-06T10:20:22Z","timestamp":1281090022000},"page":"837-843","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":103,"title":["A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinoma"],"prefix":"10.1038","volume":"17","author":[{"given":"B","family":"Sangro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Mazzolini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Ruiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Ruiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Quiroga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I","family":"Herrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Benito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Larrache","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Olag\u00fce","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Boan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I","family":"Pe\u00f1uelas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B","family":"S\u00e1daba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Prieto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2010,8,6]]},"reference":[{"key":"BFcgt201040_CR1","doi-asserted-by":"publisher","first-page":"74","DOI":"10.3322\/canjclin.55.2.74","volume":"55","author":"DM Parkin","year":"2005","unstructured":"Parkin DM, Bray F, Ferlay J, Pisani P . Global cancer statistics, 2002. CA Cancer J Clin 2005; 55: 74\u2013108.","journal-title":"CA Cancer J Clin"},{"key":"BFcgt201040_CR2","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1056\/NEJM199903113401001","volume":"340","author":"HB El-Serag","year":"1999","unstructured":"El-Serag HB, Mason AC . Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999; 340: 745\u2013750.","journal-title":"N Engl J Med"},{"key":"BFcgt201040_CR3","doi-asserted-by":"publisher","first-page":"1752","DOI":"10.1053\/j.gastro.2008.02.090","volume":"134","author":"HB El-Serag","year":"2008","unstructured":"El-Serag HB, Marrero JA, Rudolph L, Reddy KR . Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology 2008; 134: 1752\u20131763.","journal-title":"Gastroenterology"},{"key":"BFcgt201040_CR4","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1002\/hep.20933","volume":"42","author":"J Bruix","year":"2005","unstructured":"Bruix J, Sherman M . Management of hepatocellular carcinoma. Hepatology 2005; 42: 1208\u20131236.","journal-title":"Hepatology"},{"key":"BFcgt201040_CR5","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1093\/jnci\/djn134","volume":"100","author":"JM Llovet","year":"2008","unstructured":"Llovet JM, Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008; 100: 698\u2013711.","journal-title":"J Natl Cancer Inst"},{"key":"BFcgt201040_CR6","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1056\/NEJMoa0708857","volume":"359","author":"JM Llovet","year":"2008","unstructured":"Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378\u2013390.","journal-title":"N Engl J Med"},{"key":"BFcgt201040_CR7","doi-asserted-by":"publisher","first-page":"3866","DOI":"10.1038\/sj.onc.1209550","volume":"25","author":"MA Avila","year":"2006","unstructured":"Avila MA, Berasain C, Sangro B, Prieto J . New therapies for hepatocellular carcinoma. Oncogene 2006; 25: 3866\u20133884.","journal-title":"Oncogene"},{"key":"BFcgt201040_CR8","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1517\/14712598.2.2.163","volume":"2","author":"L Mohr","year":"2002","unstructured":"Mohr L, Geissler M, Blum HE . Gene therapy for malignant liver disease. Expert Opin Biol Ther 2002; 2: 163\u2013175.","journal-title":"Expert Opin Biol Ther"},{"key":"BFcgt201040_CR9","doi-asserted-by":"publisher","first-page":"13","DOI":"10.2174\/1566523033347426","volume":"3","author":"C Fillat","year":"2003","unstructured":"Fillat C, Carrio M, Cascante A, Sangro B . Suicide gene therapy mediated by the Herpes Simplex virus thymidine kinase gene\/Ganciclovir system: fifteen years of application. Curr Gene Ther 2003; 3: 13\u201326.","journal-title":"Curr Gene Ther"},{"key":"BFcgt201040_CR10","doi-asserted-by":"publisher","first-page":"975","DOI":"10.1038\/sj.cgt.7700946","volume":"13","author":"Y Shen","year":"2006","unstructured":"Shen Y, Nemunaitis J . Herpes simplex virus 1 (HSV-1) for cancer treatment. Cancer Gene Ther 2006; 13: 975\u2013992.","journal-title":"Cancer Gene Ther"},{"key":"BFcgt201040_CR11","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1517\/14712598.4.4.519","volume":"4","author":"G Vassaux","year":"2004","unstructured":"Vassaux G, Martin-Duque P . Use of suicide genes for cancer gene therapy: study of the different approaches. Expert Opin Biol Ther 2004; 4: 519\u2013530.","journal-title":"Expert Opin Biol Ther"},{"issue":"Suppl 3","key":"BFcgt201040_CR12","first-page":"S490","volume":"10","author":"T Matthews","year":"1998","unstructured":"Matthews T, Boehme R . Antiviral activity and mechanism of action of ganciclovir. Rev Infect Dis 1998; 10 (Suppl 3): S490\u2013S494.","journal-title":"Rev Infect Dis"},{"key":"BFcgt201040_CR13","first-page":"5276","volume":"46","author":"FL Moolten","year":"1986","unstructured":"Moolten FL . Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a prospective cancer control strategy. Cancer Res 1986; 46: 5276\u20135281.","journal-title":"Cancer Res"},{"key":"BFcgt201040_CR14","first-page":"5274","volume":"53","author":"SM Freeman","year":"1993","unstructured":"Freeman SM, Abboud CN, Whartenby KA, Packman CH, Koeplin DS, Moolten FL et al. The \u201cbystander effect\u201d: tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res 1993; 53: 5274\u20135283.","journal-title":"Cancer Res"},{"key":"BFcgt201040_CR15","doi-asserted-by":"publisher","first-page":"1807","DOI":"10.1089\/hum.1997.8.15-1807","volume":"8","author":"AR Kianmanesh","year":"1997","unstructured":"Kianmanesh AR, Perrin H, Panis Y, Fabre M, Nagy HJ, Houssin D et al. A \u201cdistant\u201d bystander effect of suicide gene therapy: regression of nontransduced tumors together with a distant transduced tumor. Hum Gene Ther 1997; 8: 1807\u20131814.","journal-title":"Hum Gene Ther"},{"key":"BFcgt201040_CR16","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1002\/(SICI)1097-0215(19991029)83:3<374::AID-IJC13>3.0.CO;2-#","volume":"83","author":"S Kuriyama","year":"1999","unstructured":"Kuriyama S, Kikukawa M, Masui K, Okuda H, Nakatani T, Akahane T et al. Cancer gene therapy with HSV-tk\/GCV system depends on T-cell-mediated immune responses and causes apoptotic death of tumor cells in vivo. Int J Cancer 1999; 83: 374\u2013380.","journal-title":"Int J Cancer"},{"key":"BFcgt201040_CR17","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1089\/hum.1997.8.3-349","volume":"8","author":"C Qian","year":"1997","unstructured":"Qian C, Idoate M, Bilbao R, Sangro B, Bru\u00f1a O, V\u00e1zquez J et al. Gene transfer and therapy with adenoviral vector in rats with diethylnitrosamine-induced hepatocellular carcinoma. Hum Gene Ther 1997; 8: 349\u2013358.","journal-title":"Hum Gene Ther"},{"key":"BFcgt201040_CR18","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1038\/sj.cgt.7700175","volume":"7","author":"R Bilbao","year":"2000","unstructured":"Bilbao R, G\u00e9rolami R, Bralet MP, Qian C, Tran PL, Tennant B et al. Transduction efficacy, antitumoral effect, and toxicity of adenovirus-mediated herpes simplex virus thymidine kinase\/ganciclovir therapy of hepatocellular carcinoma: the woodchuck animal model. Cancer Gene Ther 2000; 7: 657\u2013662.","journal-title":"Cancer Gene Ther"},{"key":"BFcgt201040_CR19","first-page":"118","volume":"22","author":"C Qian","year":"1995","unstructured":"Qian C, Bilbao R, Bruna O, Prieto J . Induction of sensitivity to ganciclovir in human hepatocellular carcinoma cells by adenovirus-mediated gene transfer of herpes simplex virus thymidine kinase. Hepatology 1995; 22: 118\u2013123.","journal-title":"Hepatology"},{"key":"BFcgt201040_CR20","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1089\/104303403321467225","volume":"14","author":"M Herraiz","year":"2003","unstructured":"Herraiz M, Beraza N, Solano A, Sangro B, Montoya J, Qian C et al. Liver failure caused by herpes simplex virus thymidine kinase plus ganciclovir therapy is associated with mitochondrial dysfunction and mitochondrial DNA depletion. Hum Gene Ther 2003; 14: 463\u2013472.","journal-title":"Hum Gene Ther"},{"key":"BFcgt201040_CR21","doi-asserted-by":"publisher","first-page":"13891","DOI":"10.1073\/pnas.94.25.13891","volume":"94","author":"H Su","year":"1997","unstructured":"Su H, Lu R, Chang JC, Kan YW . Tissue-specific expression of herpes simplex virus thymidine kinase gene delivered by adeno-associated virus inhibits the growth of human hepatocellular carcinoma in athymic mice. Proc Natl Acad Sci USA 1997; 94: 13891\u201313896.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFcgt201040_CR22","doi-asserted-by":"publisher","first-page":"1787","DOI":"10.1053\/j.gastro.2005.03.024","volume":"128","author":"I Penuelas","year":"2005","unstructured":"Penuelas I, Mazzolini G, Bo\u00e1n JF, Sangro B, Mart\u00ed-Climent J, Ruiz M et al. Positron emission tomography imaging of adenoviral-mediated transgene expression in liver cancer patients. Gastroenterology 2005; 128: 1787\u20131795.","journal-title":"Gastroenterology"},{"key":"BFcgt201040_CR23","unstructured":"WHO: Handbook of Reporting Results of Cancer Treatment 1979. Publication No. 48. WHO: Geneva, Switzerland."},{"key":"BFcgt201040_CR24","unstructured":"National Cancer Institute: Guidelines for the Reporting of Adverse Drug Reactions. National Cancer Institute: Bethesda, MD, 1990, pp 1\u201380."},{"key":"BFcgt201040_CR25","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.1001\/jama.1975.03260250028021","volume":"234","author":"FE Karch","year":"1975","unstructured":"Karch FE, Lasagna L . Adverse drug reactions. A critical review. JAMA 1975; 234: 1236\u20131241.","journal-title":"JAMA"},{"key":"BFcgt201040_CR26","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/S1536-1632(02)00086-0","volume":"4","author":"I Penuelas","year":"2002","unstructured":"Penuelas I, Bo\u00e1n JF, Mart\u00ed-Climent JM, Barajas MA, Narvaiza I, Satyamurthy N et al. A fully automated one pot synthesis of 9-(4-[18F]fluoro-3-hydroxymethylbutyl) guanine for gene therapy studies. Mol Imaging Biol 2002; 4: 415\u2013424.","journal-title":"Mol Imaging Biol"},{"key":"BFcgt201040_CR27","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1016\/S0168-8278(01)00130-1","volume":"35","author":"J Bruix","year":"2001","unstructured":"Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL Conference. European Association for the Study of the Liver. J Hepatol 2001; 35: 421\u2013430.","journal-title":"J Hepatol"},{"key":"BFcgt201040_CR28","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1056\/NEJM199605023341809","volume":"334","author":"JM Wilson","year":"1996","unstructured":"Wilson JM . Adenoviruses as gene-delivery vehicles. N Engl J Med 1996; 334: 1185\u20131187.","journal-title":"N Engl J Med"},{"key":"BFcgt201040_CR29","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/S0168-8278(00)80073-2","volume":"32","author":"M Drozdzik","year":"2000","unstructured":"Drozdzik M, Qian C, Xie X, Peng D, Bilbao R, Mazzolini G et al. Combined gene therapy with suicide gene and interleukin-12 is more efficient than therapy with one gene alone in a murine model of hepatocellular carcinoma. J Hepatol 2000; 32: 279\u2013286.","journal-title":"J Hepatol"},{"key":"BFcgt201040_CR30","doi-asserted-by":"publisher","first-page":"5847","DOI":"10.1158\/1078-0432.CCR-07-0499","volume":"13","author":"N Li","year":"2007","unstructured":"Li N, Zhou J, Weng D, Zhang C, Li L, Wang B et al. Adjuvant adenovirus-mediated delivery of herpes simplex virus thymidine kinase administration improves outcome of liver transplantation in patients with advanced hepatocellular carcinoma. Clin Cancer Res 2007; 13: 5847\u20135854.","journal-title":"Clin Cancer Res"},{"key":"BFcgt201040_CR31","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1006\/mthe.2001.0444","volume":"4","author":"MW Sung","year":"2001","unstructured":"Sung MW, Yeh HC, Thung SN, Schwartz ME, Mandeli JP, Chen SH et al. Intratumoral adenovirus-mediated suicide gene transfer for hepatic metastases from colorectal adenocarcinoma: results of a phase I clinical trial. Mol Ther 2001; 4: 182\u2013191.","journal-title":"Mol Ther"},{"issue":"Suppl 2","key":"BFcgt201040_CR32","doi-asserted-by":"publisher","first-page":"S384","DOI":"10.1007\/s00259-005-1928-3","volume":"32","author":"I Penuelas","year":"2005","unstructured":"Penuelas I, Haberkorn U, Yaghoubi S, Gambhir SS . Gene therapy imaging in patients for oncological applications. Eur J Nucl Med Mol Imaging 2005; 32 (Suppl 2): S384\u2013S403.","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"BFcgt201040_CR33","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/S1095-0397(01)00072-3","volume":"4","author":"B Sangro","year":"2002","unstructured":"Sangro B, Qian C, Ruiz J, Prieto J . Tracing transgene expression in cancer gene therapy: a requirement for rational progress in the field. Mol Imaging Biol 2002; 4: 27\u201333.","journal-title":"Mol Imaging Biol"},{"key":"BFcgt201040_CR34","first-page":"3016","volume":"61","author":"A Ido","year":"2001","unstructured":"Ido A, Uto H, Moriuchi A, Nagata K, Onaga Y, Onaga M 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 2001; 61: 3016\u20133021.","journal-title":"Cancer Res"},{"key":"BFcgt201040_CR35","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1016\/S0360-3016(01)01692-3","volume":"51","author":"BS Teh","year":"2001","unstructured":"Teh BS, Aguilar-Cordova E, Kernen K, Chou CC, Shalev M, Vlachaki MT et al. Phase I\/II trial evaluating combined radiotherapy and in situ gene therapy with or without hormonal therapy in the treatment of prostate cancer--a preliminary report. Int J Radiat Oncol Biol Phys 2001; 51: 605\u2013613.","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"BFcgt201040_CR36","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1016\/j.jhep.2004.12.037","volume":"42","author":"AL Stefani","year":"2005","unstructured":"Stefani AL, Barzon L, Castagliuolo I, Guido M, Pacenti M, Parolin C et al. Systemic efficacy of combined suicide\/cytokine gene therapy in a murine model of hepatocellular carcinoma. J Hepatol 2005; 42: 728\u2013735.","journal-title":"J Hepatol"},{"key":"BFcgt201040_CR37","doi-asserted-by":"publisher","first-page":"1301","DOI":"10.1053\/j.gastro.2006.02.020","volume":"130","author":"T Torimura","year":"2006","unstructured":"Torimura T, Ueno T, Kin M, Taniguchi E, Nakamura T, Inoue K et al. Gene transfer of kringle 1-5 suppresses tumor development and improves prognosis of mice with hepatocellular carcinoma. Gastroenterology 2006; 130: 1301\u20131310.","journal-title":"Gastroenterology"},{"key":"BFcgt201040_CR38","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1038\/sj.gt.3302598","volume":"13","author":"K Shinozaki","year":"2006","unstructured":"Shinozaki K, Suominen E, Carrick F, Sauter B, K\u00e4h\u00e4ri VM, Lieber A et al. Efficient infection of tumor endothelial cells by a capsid-modified adenovirus. Gene Ther 2006; 13: 52\u201359.","journal-title":"Gene Ther"}],"container-title":["Cancer Gene Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/cgt201040.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/cgt201040","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/cgt201040.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,22]],"date-time":"2022-03-22T11:42:52Z","timestamp":1647949372000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/cgt201040"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,8,6]]},"references-count":38,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2010,12]]}},"alternative-id":["BFcgt201040"],"URL":"https:\/\/doi.org\/10.1038\/cgt.2010.40","relation":{},"ISSN":["0929-1903","1476-5500"],"issn-type":[{"value":"0929-1903","type":"print"},{"value":"1476-5500","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,8,6]]},"assertion":[{"value":"6 December 2009","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 February 2010","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 April 2010","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 August 2010","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}