Improvement of human tumor xenograft-mouse model as a preclinical evaluation system of new drugs discovered and developed by the novel strategy against cancer

人类肿瘤异种移植小鼠模型的改进作为抗癌新策略发现和开发的新药的临床前评价系统

• 批准号: 08458278
• 负责人: OHNISHI Yasuyuki
• 金额: $ 1.73万
• 依托单位: Central Institute for Experimental Animals
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08458278/
• 关键词: xenograft; mouse; ribozyme; vascular endotherial growth factor; xenotransplantability; epidermal growth factor receptor; c-erb Bhuman neoplasm; C-erb B; 乳酸脱水素酵素ウイルス; GM-CSF; トランスジェニック; 血管内皮増殖因子; P-glycoprotein; ヌードマウス; SCIDマウス; アイソフォーム; G-

In the recent strategy for treatment of cancer disease, concepts such as inhibition of oncogene activity, control of invasion and metastasis of cancer cells were attentioned as a novel target.To apply human tumor xenograft (HTX) model to the evaluation of new drugs which are discovered by those concepts, we improved host mouse and procedures of implantation of HTX.We also analyzed gene expression related to progress of carcinogenecity and malignancy of neoplasm.We established double mutant mice for athymic nude (nu) and severe combined immune deficient (scid) genes.This allowed us that human skin was implanted more efficiently in the mice than in nude mouse.We first developed human skin grafted-mice using these double mutant mice, then HTX was implanted into the human skin.The tumor grew in the skin, and moreover focused in the liver of host mice.We established HTX-mouse model which overexpressed c-erbB-2/HER2 gene, and evaluated monoclonal antibody against C-ErbB-2/HER2 products.We analyzed expression of isoforms of vascular endothelial growth factor (EGER) gene in the HTXs, and found that expression of VEGF 189 in tumor tissue was related to xenotransplantability to SCID mice.

在最近的癌症治疗策略中，抑制癌基因活性、控制癌细胞的侵袭和转移等概念被作为一个新的靶点而受到关注。为了将人类肿瘤异种移植(HTX)模型应用于根据这些概念发现的新药的评价，我们改进了宿主小鼠和HTX的植入程序。我们还分析了与肿瘤的致癌和恶性进展相关的基因表达。我们建立了裸鼠和严重联合免疫缺陷(SCID)基因的双突变小鼠。这使得我们能够更有效地将人皮肤移植到小鼠体内。我们首先利用这些双突变小鼠培育了人皮肤移植小鼠，然后将HTX移植到人皮肤中。肿瘤在皮肤中生长，并集中在宿主小鼠的肝脏。我们建立了高表达c-erbB-2/HER2基因的HTX-小鼠模型，并对C-ErbB-2/HER2的单抗进行了鉴定。我们分析了血管内皮生长因子(Eger)基因的异构体在HTX中的表达，发现VEGF189在肿瘤组织中的表达与SCID小鼠的异种移植能力有关。

项目成果

Toknaga,T: "Is xenotransplantability of human colon cancers in SCID mice affected by angiogenic factors?" J.Natl.Cancer Inst.90. 400-401 (1998)

Toknaga,T：“SCID 小鼠中人类结肠癌的异种移植性是否受到血管生成因子的影响？”

Yoshimura,M: "Quarantin for contaminated pathogens in transplantable human tomors or infection in tumer bearing mice" Expr.Anim.46. 161-164 (1997)

Yoshimura,M：“隔离可移植人类肿瘤中受污染的病原体或荷瘤小鼠中的感染”Expr.Anim.46。

Oshika, Y., et al.: "A human lung cancer xenograft producing granulocyte-colony stimulating factor and parathyroid hormone-related protein." Oncol. Rep. 5. 359-362 (1998)

Oshika, Y. 等人：“一种产生粒细胞集落刺激因子和甲状旁腺激素相关蛋白的人肺癌异种移植物。”

Abe, Y., et al.: "Advantage of in vivo chemosensitivity assay to detect vincristine-resistance in a human epidermoid carcinoma xenograft." AntiCancer Res.16. 729-734 (1996)

Abe, Y. 等人：“体内化学敏感性测定检测人表皮样癌异种移植物中长春新碱耐药性的优势。”

Masumi Yoshimura: "Chemotherapeutic profiles of human tumors implanted in SCID mice showing appeciable inconsistencies with those in nude mice" Expr.Anim.46. 153-156 (1997)

Masumi Yoshimura：“植入 SCID 小鼠体内的人类肿瘤的化疗曲线与裸鼠中的化疗曲线明显不一致”Expr.Anim.46。