Rosenfeld M E, Rogers B E, Khazaeli M B, Mikheeva G, Raben D, Mayo M S, Curiel D T, Buchsbaum D J
Medical Genetics Program, Gene Therapy Program, University of Alabama, Birmingham, Alabama 35294, USA.
Clin Cancer Res. 1997 Jul;3(7):1187-94.
Radioimmunotherapy is hindered by a variety of factors linked to the utilization of monoclonal antibodies. These limitations include restricted tumor penetration as well as low levels of intratumoral antigen expression. To address the latter problem, we used a gene therapy approach to induce tumor cells to express enhanced levels of receptor with high binding affinity for a radiolabeled peptide. In this regard, a radiolabeled bombesin analogue was used in conjunction with a recombinant adenoviral vector encoding the murine gastrin-releasing peptide receptor (mGRPr). A panel of human carcinoma cell lines was infected in vitro with the recombinant adenoviral vector encoding the mGRPr vector to examine the induced binding of a 125I-labeled bombesin peptide. All cell lines examined displayed high levels of induced peptide binding, with approximately 60-80% of the radioactivity bound to the cells, in a live-cell binding assay. The human ovarian carcinoma cell line SKOV3.ip1 was chosen for in vivo analysis of radiolabeled bombesin analogue tumor localization in biodistribution and pharmacokinetic studies in athymic nude mice. Genetic induction of mGRPr in vivo resulted in selective tumor uptake of the radiolabeled peptide and high tumor:blood ratios. The biodistribution results compared favorably to those obtained with 131I-labeled e21 anti-erbB-2 monoclonal antibody in animals bearing i.p. SKOV3.ip1 tumors that endogenously express erbB-2. Thus, a novel method to combine gene transfer and radioimmunotherapy may result in augmented tumor cell targeting of radiopharmaceuticals.
放射免疫疗法受到与单克隆抗体应用相关的多种因素的阻碍。这些限制包括肿瘤穿透受限以及肿瘤内抗原表达水平较低。为了解决后一个问题，我们采用了一种基因治疗方法，诱导肿瘤细胞表达对放射性标记肽具有高结合亲和力的增强型受体水平。在这方面，一种放射性标记的蛙皮素类似物与编码鼠胃泌素释放肽受体（mGRPr）的重组腺病毒载体联合使用。用编码mGRPr载体的重组腺病毒载体在体外感染一组人癌细胞系，以检测125I标记的蛙皮素肽的诱导结合。在活细胞结合试验中，所有检测的细胞系均显示出高水平的诱导肽结合，约60 - 80%的放射性与细胞结合。在无胸腺裸鼠的生物分布和药代动力学研究中，选择人卵巢癌细胞系SKOV3.ip1进行放射性标记蛙皮素类似物肿瘤定位的体内分析。体内mGRPr的基因诱导导致放射性标记肽在肿瘤中的选择性摄取以及高肿瘤与血液比值。在携带内源性表达erbB - 2的腹腔SKOV3.ip1肿瘤的动物中，生物分布结果与用131I标记的e21抗erbB - 2单克隆抗体获得的结果相比更有利。因此，一种将基因转移和放射免疫疗法相结合的新方法可能会增强放射性药物对肿瘤细胞的靶向作用。
