| Project/Area Number |
09670612
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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 |
Respiratory organ internal medicine
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| Research Institution | OSAKA UNIVERSITY |
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Principal Investigator |
HAYASHI Seiji Osaka University Medical School, Depariment of Medicine III, 医学部, 講師 (70218577)
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| Co-Investigator(Kenkyū-buntansha) |
KIJIMA Takashi Osaka University Hospital, Department of Medicine III,Medical Staff, 医学部・附属病院, 医員
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1998: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1997: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | Lung cancer / HSV-tk / CEA promoter / Cre / loxP system / myc oncogene / ganciclovir (GCV) / nonproliferating adenoviral vector / 非増殖型アデノウイルスベクター |
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| Research Abstract |
(1) Gene therapy specific for CEA-producing lung cancer
Rejection of CEA-producing tumors was not observed by intra-tumoral injection with a recombinant adenoviral vector (Ad.) expressing the HSV-tk gene under the CEA promoter (Ad.CEA-TK) followed by ganciclovir (GCV) treatment in vivo.It is conceivable that the low activity of the CPA promoter results in insufficient expression of the HSV-tk gene in cancer cells as well as in insignificant antitumor effects.To obtain enhanced expression of the HSV-tk gene exclusively in tumor cells and subsequent significant in vivo antitumor effects, we applied the Cre/loxP system to HSV-tk/GCV therapy for CEA-producing cancer.We constructed an Ad producing Cre recombinase driven by the CEA promoter (Ad.CEA-Cre) and another Ad designed for inducible expression of the HSV-tk gene by Cre (Ad.CAG-loxP-TK).Co-infection by these Ads rendered a human CEA-producing cancer cell line 8.4-fold more sensitive to GCV compared with infection by Ad.CEA-TK alone.On
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the other hand, co-infection with these Ads did not significantly change GCV sensitivity of CEA-non-producing cells.Intra-tumoral injection of Ad.CEA-Cre combined with Ad.CAG-loxP-TK followed by GCV treatment completely eradicated CEA-producing tumors established in the subcutis of 6 out of 7 athymic mice, whereas injection of Ad.CEA-TK alone with GCV administration at most retarded the growth of inoculated tumors.These results suggest distinct advantages of the Cre/loxP system applied in the conventional cell type-specific gene therapy against cancer.We are now evaluating the efficacy and side effects of this system in the peritonitis carcinomatosa model in mice, mimicking pleuritis for lung cancer in future clinical applications to human beings.
(2) Gene therapy specific for Myc-overexpressing small cell lung cancer (Myc-SCLC)
We previousely reported that an Ad. containing the HSV-tk gene ligated with the Myc-binding motif (Ad.Myc-TK) showed a cell-type specific expression of the HSV-tk gene in Myc-SCLC cell lines.We analyzed the efficacy of the intraperitoneal injection of Ad.Myc-TK followed by GCV treatment on Myc-SCLC inoculated in the peritoneal cavity of athymic mice.This treatment successfully reduced the weight of tumors to one fourteenth of that of untreated mice and completely eradicated tumors in 2 of 8 mice. Less
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