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Tissue‐specific expression of HSV‐ tk gene can induce efficient antitumor effect and protective immunity to wild‐type hepatocellular carcinoma
Author(s) -
Kuriyama Shigeki,
Sakamoto Takemi,
Masui Kazuhiro,
Nakatani Toshiya,
Tominaga Kentaro,
Kikukawa Masaji,
Yoshikawa Masahide,
Ikenaka Kazuhiro,
Fukui Hiroshi,
Tsujii Tadasu
Publication year - 1997
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19970502)71:3<470::aid-ijc27>3.0.co;2-i
Subject(s) - ganciclovir , genetic enhancement , thymidine kinase , biology , virology , herpes simplex virus , suicide gene , cancer research , hepatocellular carcinoma , viral vector , in vivo , virus , microbiology and biotechnology , gene , human cytomegalovirus , biochemistry , recombinant dna
The efficacy of expression of the herpes simplex virus thymidine kinase (HSV‐ tk ) gene under the transcriptional control of the liver‐specific albumin gene promoter, followed by ganciclovir treatment, was investigated both in vitro and in vivo. Murine and rat hepatocellular carcinoma (HCC) cells infected with retroviruses carrying the HSV‐ tk gene under the control of the murine albumin gene promoter were selectively killed by ganciclovir treatment in vitro, whereas non‐HCC cells, such as murine mammary tumor cells and fibroblast cells, which were infected with the same retroviruses, were not. Susceptibility of the retroviral‐infected HCC cells to ganciclovir was more than 100‐fold higher than that of the retroviral‐infected non‐HCC cells. When mice bearing a bulky HCC mass consisting of the retroviral‐infected HCC cells were treated with systemic ganciclovir administration, complete regression of the tumors was observed without any signs of overt toxicity. Profound antitumor effects on preestablished murine HCCs were observed when wild‐type HCC cells were implanted into animals with a small percentage of the retroviral‐infected counterparts. When only 5% of the cells were infected with retroviruses carrying the HSV‐ tk gene, significant inhibition of tumor development was observed with systemic ganciclovir treatment. Importantly, animals that were treated with implantation of mixtures of the retroviral‐infected and parental HCC cells, followed by ganciclovir administration, did not exhibit tumor formation and resisted subsequent rechallenge with wild‐type HCC cells. Our results indicate the feasibility of combination therapy with the HSV‐ tk gene and ganciclovir for the treatment of HCC. Int. J. Cancer 71:470‐475, 1997. © 1997 Wiley‐Liss Inc.