Co-transduction of herpes simplex virus thymidine kinase gene and human interleukin-2 gene into mouse ovarian cancer cell line, OVHM.
We studied the thymidine kinase (TK) gene and the interleukin (IL)-2 gene co-transduction into tumor cells for a possible strategy of cancer gene therapy. A murine ovarian cancer cell line, OVHM, was retrovirally transduced with the TK (OVHM/TK) or the IL-2 gene (OVHM/IL-2). The TK or IL-2 expression was permanent in OVHM/TK or OVHM/IL-2. OVHM/TK cells were susceptible to gancyclovir (GCV) in vitro, and their intraperitoneal growth was completely regulated with GCV administration. The bystander effect was not observed in vitro and in vivo in this model, and only the marginal emergence of immune involvement was observed in the OVHM/TK-cured mice with GCV. OVHM/IL-2 cells produced IL-2 biologically active to be immunogenic, but still tumorigenic to kill the mice when inoculated intraperitoneally. Then, OVHM/TK cells were co-transduced with the IL-2 gene to establish OVHM/TK/IL-2 cells. OVHM/TK/IL-2 cells were also susceptible to GCV and transiently produced active IL-2. A significant resistance against the challenge of parental tumor cells was observed in the mice that were inoculated with OVHM/TK/IL-2 cells and cured with GCV administration. It is suggested that tumor cells transduced with both TK and IL-2 genes could be regressed with GCV administration with subsequent generation of immune activation in the host. Since the bystander effect may not always be a common phenomenon in gene therapy using the TK gene, this type of combination may be advantageous in the clinical application of gene therapy for human cancers.
Yamaguchi
Y
Y
Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Minami-ku, Hiroshima 734-8553, Japan.
Takashima
I
I
Hihara
J
J
Ohta
K
K
Shimizu
K
K
Minami
K
K
Yoshida
K
K
Toge
T
T
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D015152:Blotting, Northern; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic; D005260:Female; D015774:Ganciclovir / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D005818:Genetic Engineering; D015316:Genetic Therapy; D006801:Humans; D007274:Injections, Intraperitoneal; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D018139:Simplexvirus / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; D007376:Interleukin-2; D013937:Thymidine Kinase; D015774:Ganciclovir