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Combination of gene therapy with targeting-radio-therapy against prostate cancer using anti-PSA antibody

使用抗 PSA 抗体联合基因治疗与靶向放射治疗治疗前列腺癌

基本信息

批准号：
09470344
负责人：
KOSHIDA Kiyoshi
金额：
$ 1.15万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470344/
关键词：
prostate cancer Gene therapy Targeting radiotherapy 標的放射線療法

项目摘要

Sensitivity of human prostate cancer cell lines : LNCaP, DU-145, PC-3 to 5FU in vitro was as follows ; LNCaP>DU-145>PC-3. Cytotoxic effect of 5FC to these cell lines to which cytosine deaminase gene was transfected, was shown for only LNCaP/CD, mostly depending on the efficiency of gene transfection. The order of sensitivity to 5FC was the same as that of intact cell lines to 5FU following selection of these cells with G418. Then we developed an in vivo model by injection of LNCaP or LNCaP/CD cells into the testis of SCID mice. A significant anti-tumor effect was shown by systemic administration of 15 mg/kg, 30 mg/kg of 5FU with mild weight loss. Also equivalent anti-tumor effect was shown for LNCaP/CD tumor by administration of 5FC without weight loss. The tissue and serum concentration of 5FU corresponded to the anti-tumor effect and the adverse reaction observed. This might represent the advantages of the gene therapy. Then the potential of combination with radioimmunotherapy was investigated. I-131 labeled anti-PSA Ab was injected following 5FC administration to enhance anti-tumor effect. However, no anti-tumor effect was obtained in combination of RIT and gene therapy, probably due to poor accumulation of the Ab to tumors. We need dose escalation study of I-131 labeled Ab and to improve the specificity of the Ab as well.

人前列腺癌细胞系LNCaP、DU-145、PC-3对5-FU的体外敏感性依次为：LNCaP>DU-145>PC-3。5 FC对转染胞嘧啶脱氨酶基因的细胞系的细胞毒性作用仅在LNCaP/CD中显示，主要取决于基因转染的效率。在用G418选择这些细胞后，对5 FC的敏感性顺序与完整细胞系对5 FU的敏感性顺序相同。在此基础上，我们建立了一种将LNCaP或LNCaP/CD细胞注射到SCID小鼠睾丸中的体内模型。全身给予15 mg/kg、30 mg/kg的5 FU显示出显著的抗肿瘤作用，伴有轻度体重减轻。通过给予5 FC而不减轻体重，也显示了对LNCaP/CD肿瘤的等效抗肿瘤作用。5 FU的组织和血清浓度与抗肿瘤作用和观察到的不良反应相对应。这可能代表了基因治疗的优势。然后研究与放射免疫治疗联合的可能性。在5 FC给药后注射I-131标记的抗PSA Ab以增强抗肿瘤作用。然而，在RIT和基因治疗的组合中没有获得抗肿瘤效果，可能是由于抗体对肿瘤的不良积累。因此，需要对131标记的抗体进行剂量递增研究，并提高抗体的特异性。