2001 Fiscal Year Final Research Report Summary
Enhancement of anticancer effects by HSV-TK potentiators and evaluation of navel liposome vectors in MSV-TK/prodding gene therapy
| Project/Area Number |
12672210
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY |
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Principal Investigator |
HAYASHI Kyoko Toyama Medical and Pharmaceutical university, Faculty of Medicine Assistant Professor, 医学部, 助手 (60110623)
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| Co-Investigator(Kenkyū-buntansha) |
MAITANI Yoshie Hoshi University, Faculty of pharmaceutical Sciences Professor, 薬学部, 教授 (10231581)
HAYASHI Toshimitsu Toyama Medical and Pharmaceutical university, Faculty of Pharmaceutical Sciences Professor, 薬学部, 教授 (40092796)
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| Project Period (FY) |
2000 – 2001
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| Keywords | cancer gene therapy / herpes simplex virus / thymidine kinase / acyclovir / ganciclovir / ponicidin / scepadulciol / liposome vector |
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| Research Abstract |
In cancer gene therapy trials, herpes simplex virus-specific thymidine kinase (HSV-TK) has been used as a suicide gene in the presence of ganciclovir (GCV) or acyclovir (ACV). Two diterpenoids, scopadulciol (SDC) and ponicidin (PND), stimulated selectively the HSV-TK enzymatic activity. Thus, we studied the potentiation of GCV/ACV toxicity by these compounds in HSV-TK-expressing cancer cells. The results obtained were as follows:
1) Transfectants: Human cancer cells were transfected with the plasmid containing HSV-l tk gene. After cloning, stably HSV-TK-expressing (TK^+) cell clones were obtained. These transfectants showed the ability of forming tumors in nude mice.
2) In vivo anticancer effects: The in vivo growth of TK^+ cells was significantly inhibited by coadministration of SDC/PND and ACV, or of SDC/PND and GCV, compared with single administration of ACV or GCV in spite of lower doses.
3) Bystander effects: The abilities of SDC and PND to potentiate the bystander effects of the products were determined in both in vitro and in vivo systems. In vitro combined use of SDC/PND. With ACV/GCV rendered tumor cells more sensitive to the prodrugs as compared with the prodrug only in 1 to 20% of TK^+ cells. In the in vivo experiments using nude mice injected with 3 or 10% TK^+ cells, significant reduction in tumor volume was observed in mice treated with drug combinations as compared with those treated with the produg only.
4) Toxicity and efficacy: No toxicity of both SDC and PND was seen in mice even at a dose 10-fold higher than that used in the in vivo experiments. SDC has more potent effects than PND, and the possibility for stable supply from organ cultures of the plant.
5) Evaluation of the efficiency of liposome vectors: Transfection efficiency of the gene by cationic liposome was increased in the presence of soybean-derived sterylglucoside. The liver targeting was also improved by this liposome.
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