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論文 |
論文
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Nodagashira, Tatsuya ; Odagiri, Hiroki ; Ikenaga, Shojiro-Kazunori ; Maruyama, Masateru ; Sato, Toshiyuki ; Hakamada, Kenichi
概要:
Tissue-specifi c promoter has been used for cancer-specifi c suicide gene therapy, but its transcriptionalactivity is r
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elatively low. For more effi cient gene therapy of HER2-expressing tumor, a double adenovirus infectionsystem was established, in which a ‘regulator’ vector carried Cre gene under the control of HER2 promoter and ‘target’vectors carried target genes activated by Cre. We constructed a Cre recombinase expression vector, AxHER2Cre, forthe ‘regulator’ vector. By the combination of this vector and AxCALNLZ, β-D-galactosidase was induced in 90% and70% of MKN7 and MDA-MB-453, HER2‒overexpressing cell lines, but only about 20% and 10% of MKN28 and MCF7,low HER2-expressing cell lines. By the quantifi cation analysis, the β-galactosidase activities induced by this systemwere comparable to those by the combination of AxCANCre and AxCALNLZ. These results indicated that Cre/loxP system under the regulation of HER2 promoter could induce effi cient gene expression, maintaining the HER2-expression specifi city. Breast cancer with HER2 overexpression is treated with trastuzumab. However, refractoryor resitance of HER2 positive breast cancer against trastuzumab becomes a severe clinical problem, recently. Thissystem seemed to be another therapeutic option.
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| 2.
論文 |
論文
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Maruyama, Masateru ; Odagiri, Hiroki ; Ikenaga, Shojiro-Kazunori ; Nodagashira, Tatsuya ; Sato, Toshiyuki ; Hakamada, Kenichi ; Munakata, Hirofumi
概要:
We examined the therapeutic efficacy for the suicide gene introduction using two recombinant adenovirusvectors with HER2
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promoter and Cre/loxP system in human gastric cancer cell lines, MKN-7 and MKN-28. HER2protein level was more expressed in MKN-7 than in MKN-28. Next, we constructed a Cre recombinae expressionvector in HER2-producing cell specifically, AxHER2NCre and AxCALNCD expressing cytosine deaminase （CD）gene under the control of the CAG promoter by the Cre switching system. Much higher CD messenger RNA （CDmRNA） and CD protein expression were induced in cells by the double infection method than by AxCALNCD only.Furthermore, CD mRNA and CD protein expression were induced higher in HER2-overexpressing cell line, MKN-7 than in MKN-28. We examined the efficacy of cell growth inhibition using 5-fluorocytosine （5-FC） as anti-tumorprodrug. Inhibition effect was dose-dependent at each cell line and rate was more in MKN-7 in comparison withMKN-28. This system can be applied for HER2-overexpressing cancer specific gene therapy.
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