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Super-p53を用いた新しいがん遺伝子治療法の開発

使用 Super-p53 开发新的癌症基因疗法

基本信息

批准号：
17790432
负责人：
角道祐一
金额：
$ 2.05万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17790432/
关键词：
癌遺伝子 super p53 アポトーシス p53

项目摘要

【結果1】p53欠失ヒト腫瘍細胞株であるSaos-2を用いてスクリーニングし、新たに見つかった強力なアポトーシス誘導能をもつ変異型p53、すなわちSuper-p53をアデノウイルスに組み込んだ。これにより培養細胞およびマウス移植腫瘍に対する簡便かつ高率な遺伝子導入実験を可能にした。これらを用いて、種々の培養細胞株における細胞増殖抑制効果を調べ、癌種・p53ステータスに対応させた細胞増殖抑制効果についてパネルを作成した。この過程で、Saos-2のみでなく、その他の癌細胞株(U20S、SF126、DLD-1、HCTl16など;data not shown)においても、Super p53のアポトーシス誘導のタイミングが変異体によって若干異なることが判明した。すなわち、コドン121の変異体群はアポトーシス誘導が惹起されるタイミングが、その他の変異体と比べて有意に早いことが確認された。【結果2】細胞増殖抑制効果パネルにもとづいて、複数のがん細胞に対し、またp53のステータスにindependentに細胞増殖抑制効果を示した変異体S121Y、S121C、S121F、E221Q、R290G、K291Eについての抗腫瘍効果をin vivo(ヌードマウス皮下移植腫瘍モデル、癌性腹膜炎モデル)で検討した。【結果3】その結果、皮下移植腫瘍モデルにおいては、変異体S121Y、S121C、S121F、E221Q、R290G、E291Eは野生型p53よりも有意に強い抗腫瘍効果を認めた。しかし、癌性腹膜炎モデルにおいては、いずれの変異体も野生型p53と比較し、生存期間の有意な延長は認めず、抗腫瘍効果の増強は確認できなかった。逆に、変異体S121Y、S121C、S121Fは野生型p53に比べ、著明な体重減少と生存期間の短縮を認めた。【結論】以上の結果から、われわれが同定したSuper-p53のうち、局所治療に関しては野生型p53を上回る抗腫瘍効果をもつ変異体を複数認めたが、腹腔内投与などの全身性投与に明らかな有用性を示す変異体は認められなかった。

[results 1] the loss of p53 gene was detected in the cell strain Saos-2, and the new gene was used to induce the expression of p53. [results 1] the loss of p53 gene, cell line, cell line, cell Please tell me that there is a high rate of stool in the transplant program. Cell culture was used to induce cell colonization inhibition and cancer species. P53 cells were used to inhibit cell proliferation. Cell lines (U20s, SF126, DLD-1, HCTl16 cancer; data not shown) were tested by Saos-2, HCTl16, and Super p53 cell lines. The results showed that there were significant differences between the two groups. Please tell me that you are not aware of the situation, and that you are interested in confirming that you are not aware of your intention to do so. [results 2] the results of cell colonization inhibition showed that the cell colonization inhibition was confirmed by subcutaneous transplantation (subcutaneous transplantation) and carcinomatous peritonitis (carcinomatous peritonitis). [results 2] the results showed that the cell colonization inhibition was confirmed by cell colonization inhibition (S121Y, S121C, S121F, E221Q, R290G, K291E) in vivo (subcutaneous transplantation), cancer peritonitis (carcinomatous peritonitis). [results 3] the results of subcutaneous transplantation showed that the wild type p53 genes of S121Y, S121C, S121F, E221Q, R290G, E291E were intentionally strong. The serum levels of wild-type p53, wild-type p53 and anti-cancer peritonitis were significantly higher than those of the control group (P < 0.05). The results of anti-cancer peritonitis were significantly higher than that of wild-type p53 gene. S121Y, S121C, S121F wild-type p53 were compared, and weight loss was identified during survival. [results] the results of the above results showed that the results of the above results showed that the results of the above results were the same as the results of the above results, the results of the above results showed that the results of the above results were the same as the results of the above results, the results of the above results showed that the results of anti-