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

体外培养的人前列腺癌LNCaP、DU-145、PC-3对5FU的敏感性为：LNCaP&GT；DU-145&GT；PC-3。5FC对转染胞嘧啶脱氨酶基因的细胞株的细胞毒作用仅对LNCaP/CD细胞有明显的杀伤作用，且主要取决于基因转染率。经G418筛选后，这些细胞对5FC的敏感性顺序与完整细胞对5FU的敏感性顺序相同。然后将LNCaP或LNCaP/CD细胞注射到SCID小鼠睾丸内，建立了SCID小鼠体内模型。全身给药15 mg/kg、30 mg/kg的5-FU有明显的抗肿瘤作用，体重减轻不明显。5FC对LNCaP/CD肿瘤也有相同的抗肿瘤作用，但不减轻体重。5FU的组织浓度和血药浓度与其抗肿瘤作用和不良反应相一致。这可能代表了基因疗法的优势。并对联合放射免疫治疗的可能性进行了探讨。5FC给药后注射I-131标记的抗PSA抗体，以增强抗肿瘤作用。然而，RIT与基因治疗联合应用未见明显的抗肿瘤作用，可能是由于肿瘤抗体蓄积不足所致。我们需要对I-131标记的抗体进行剂量递增研究，并提高抗体的特异性。

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.