2001 Fiscal Year Final Research Report Summary
SUICIDEAND IMMUNE GENE THERAPY USING TUMOR SPECIFIC PROMOTOR FOR BREAST CANCER
| Project/Area Number |
12671190
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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 |
General surgery
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| Research Institution | CHIBA UNIVERSITY (2001)
Chiba Cancer Center (Research Institute) (2000) |
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Principal Investigator |
MATSUBARA Hisahiro Chiba University, University Hospital, Assistant, 医学部・附属病院, 助手 (20282486)
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| Co-Investigator(Kenkyū-buntansha) |
AGAWA Masatoshi Chiba Cancer Center, Research Institute, Head, 病理研究部, 部長 (20171572)
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| Project Period (FY) |
2000 – 2001
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| Keywords | RREAST CANCER / SUICIDE GENE THERAPY / TUMOR SPECIFIC PROMOTER / midkine / c-erbB-2 / HSV-tk |
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| Research Abstract |
A selective expression of suicide or immune gene(s) in tumor cells should produce a preferential cytotoxic effect on tumors and a useful strategy for cancer treatment. The c-erbB-2 and midkine gene are frequently overexpressed in human breast cancers as a result of gene amplification and/or elevated transcription. We therefore examined a possible usage of promoter regions of the c-erbB-2 and midkine gene to express a suicide gene preferentially in breast cancer cells. The present reporter gene assays using deletion mutants of the c-erbB-2 promoter region demonstrated that the 251-bp (-213/+38 from the transcriplional start site) but not the 125-hp fragment (-87/+38) could direct transcription of the linked luciferase gene better than the SV40 immediate early promoter in breast cancer cells. Also the 1.0 kb promoter region of the midkine gene could activate transcription of a fused reporter gene and suicide gene in human breast cancer cells. In contrast, the 251-bp fragment-mediated pro
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moter activity in nonbreast cancer cells and in normal fibroblasts was lower than the activity by the SV40 promoter. The 126-bp fragment (-213/-87) thereby contains a exacting element(s) which is responsible for the preferential transcriptional activity in breast cancer cells. An electrophoretic mobility shift assay suggested that a possible modification of a transcriptional factor was involved in the tumor specificity. Transaction with the plasmid DNA containing the herpes simplex virus-thymidine kinase gene linked with the 251-bp promoter (p256-TK) resulted in increased sensitivity to ganciclovir (GCV) in breast cancer but not in nonbreast cancer cells. Administration of GCV into nude mice bearing human breast tumors that were transfecled with the p256-TK DNA suppressed subsequent growth of the transplanted tumors. These results suggest that delivery of a suicide gene linked with the these 1.0 kb midkine or 251 bp c-erbB-2 promoter can be a feasible therapeutic strategy specific to breast cancer. Less
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