Department of Medicine, Peptide Research Laboratories, Tulane Health Sciences Center, New Orleans, LA 70112-2699, USA.
J Drug Target. 2011 Sep;19(8):666-74. doi: 10.3109/1061186X.2010.531728. Epub 2010 Nov 18.
In our previous study, we found that several tumor cell lines displayed high receptor-specific binding affinity, one of which, the human pancreatic carcinoid BON cell line, demonstrates high affinity binding of the bombesin (BN) and somatostatin (SST) receptor-specific ligands. In the present study, BON cells, as a representative model, were further applied to evaluate various peptide analogs and cytotoxic receptor-targeted peptide conjugates. We observed quick ligand-receptor internalization in BON cells as well as high binding affinity. Furthermore, BON cells have high expression of multidrug resistance-associated genes (MDR1) and show camptothecin (CPT) resistance. Various receptor-specific cytotoxic conjugates were synthesized and evaluated in the BON cell model via in vitro and in vivo studies. We found that all the tested conjugates displayed potent antitumor ability in xenografts. Especially, the CPT conjugates, CPT-SST, and CPT-BN, are most likely to increase sensitivity to CPT-resistant BON cells. Our findings suggest that appropriately defined tumor cell lines may provide physiologically relevant cell-based evaluations of novel peptide analogs and receptor-targeted chemotherapeutics.
在我们之前的研究中，我们发现一些肿瘤细胞系显示出高的受体特异性结合亲和力，其中之一是人类胰腺类癌 BON 细胞系，其表现出高亲和力结合蛙皮素（BN）和生长抑素（SST）受体特异性配体。在本研究中，BON 细胞作为代表性模型，进一步用于评估各种肽类似物和细胞毒性受体靶向肽缀合物。我们观察到 BON 细胞中配体-受体的快速内化以及高的结合亲和力。此外，BON 细胞高表达多药耐药相关基因（MDR1），并表现出喜树碱（CPT）耐药性。通过体外和体内研究，在 BON 细胞模型中合成并评估了各种受体特异性细胞毒性缀合物。我们发现所有测试的缀合物在异种移植中均显示出强大的抗肿瘤能力。特别是 CPT 缀合物 CPT-SST 和 CPT-BN 最有可能增加对 CPT 耐药 BON 细胞的敏感性。我们的研究结果表明，适当定义的肿瘤细胞系可能为新型肽类似物和受体靶向化疗药物提供生理相关的基于细胞的评估。
