| Project/Area Number |
05454435
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Urology
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| Research Institution | NIPPON MEDICAL SCHOOL |
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Principal Investigator |
AKIMOTO Masao NIPPON MEDICAL SCHOOL,DEPT.OF UROLOGY,PROFESSOR, 医学部, 教授 (50089752)
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| Co-Investigator(Kenkyū-buntansha) |
TERASHIMA Yasunori NIPPON MEDICAL SCHOOL,DEPT.OF UROLOGY,ASSISTANT PROFESSOR, 医学部, 講師 (80207480)
SUZUKI Satoru NIPPON MEDICAL SCHOOL,DEPT.OF 2ND BIOCHEMISTRY ASSISTANT, 医学部, 助手 (70246940)
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| Project Period (FY) |
1993 – 1995
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| Project Status |
Completed (Fiscal Year 1995)
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| Budget Amount *help |
¥4,600,000 (Direct Cost: ¥4,600,000)
Fiscal Year 1995: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1994: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1993: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | Renal cell carcinoma / Gene Therapy / Recombinant viral vector / suicide gene / Tumor immunity / 遺伝子治療 / 腎細胞癌 / 自殺遺伝子 / 抗腫瘍免疫 / 組換えウイルスベクター / 組換えウィルスベクター / 腫瘍免疫 / 腎癌 |
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| Research Abstract |
Transfer of the herpes simplex virus thymidine kinase (HSV-TK) gene into cancer cells followed by treatment of ganciclovir (GCV) is an important strategy of cancer gene therapy. HSV-TK transduced cells were efficiently killed with GCV-triphosphate generated from GCV by the action of HSV-TK.In addition, adjacent non-transduced tumor cells are killed by the bystander effect, althogh the mechanism of this effect is not fully understood. We addressed a question whether the systemic immune response was involved in tumor regression in vivo. TK+RENCA (renal cell carcinoma) cell lines was established using a retroviral vector containing the HSV-TK gene driven by the CMV promotor and implanted subcutaneously into BALB/c mice. After complete regression of TK+tumor cells by GCV treatment, the animals were challenged with non-transduced tumor cells.
Rejection or significant growth inhibition of challenged tumor cells was observed. The ^<51>Cr release assay of the spleen cells from the tumor rejected mice demonstrated that the tumor-reactive T cells were systemically induced. The lysis of target cells was efficiently blocked by anti-CD8 antibody but not by anti-CD4 antibody, suggesting that most of the lysis was mediated by classical CD8+ CTLs. To study the mechanism of induction of the tumor specific CTLs, we examined the expression of MHC class I molecules on tumor cells., Increased levels of class I molecules were detected specifically on HSV-TK/GCV treated cells.
These results suggested that HSV-TK/GCV system might be useful not only for short term tumor regression due to the direct cell killing and bystander effect but also for long term tumor regression and prevention of recurrence due to the vaccination effect.
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