Sun Li-Chun, Mackey L Vienna, Luo Jing, Fuselier Joseph A, Coy David H
Department of Medicine, Peptide Research Laboratories, Tulane Health Sciences Center, New Orleans, LA 70112-2699, U.S.A.
Clin Med Oncol. 2008;2:491-9. doi: 10.4137/cmo.s970. Epub 2008 Aug 19.
The major problems of traditional chemotherapy are non-selectivity and non-specificity, resulting in severe toxic side effects. Peptides are a new-generation of drug-delivery vector to increase efficacy of this therapy and avoid the resulting damage. The cytotoxic somatostatin (SST) conjugate JF-10-81 was developed by coupling camptothecin (CPT) to the N-terminus of a SST analog (JF-07-69) using an activated carbamate linker. This conjugate selectively targets somatostatin receptor subtype 2 (SSTR2) and also retains high binding affinity and rapid internalization as well as anti-proliferative activity towards various tumor cells. JF-10-81 was tested for its inhibitory activity against the growth of human tumors which included neuroblastoma (IMR32), pancreatic cancer (CFPAC-1), leukemia (MOLT-4), pancreatic carcinoid (BON) and prostate cancer (PC-3). Both SSTR2 mRNAs and proteins were detected in all these tumor cell lines. The conjugate displayed potent in vivo inhibitory activity, although some of the potency measured in in vitro experiments was lost. JF-10-81 was found to significantly inhibit growth of these SSTR-positive tumors, resulting in 87% tumor reduction in neuroblastoma IMR32 and 97% in leukemia MOLT-4 bearing animals, even inducing regression of CFPAC-1 tumors. SSTR-overexpressing BON tumors were unfortunately relatively CPT-insensitive in vitro, however, JF-10-81 again exhibited in vivo potency presumably by specifically increasing CPT concentrations inside the tumor cells so that the inhibition rate for JF-10-81 was 85%. Also, JF-10-81 was used to treat highly invasive PC-3 tumors where s.c. injections inhibited both tumor growth (almost 60% reduction) and tumor metastasis (over 70%). This conjugate demonstrated its broad and excellent anti-tumor activity by targeting SSTR2-specific tumor tissues, supporting that short peptides and their analogs may be applied as ideal drug-delivery carriers to improve the traditional chemotherapy.
传统化疗的主要问题是缺乏选择性和特异性，会导致严重的毒副作用。肽是新一代的药物递送载体，可提高这种疗法的疗效并避免由此产生的损害。细胞毒性生长抑素（SST）偶联物JF-10-81是通过使用活化的氨基甲酸酯接头将喜树碱（CPT）偶联到SST类似物（JF-07-69）的N末端而开发的。这种偶联物选择性靶向生长抑素受体2型（SSTR2），并且还保留了高结合亲和力、快速内化以及对各种肿瘤细胞的抗增殖活性。对JF-10-81进行了针对人肿瘤生长的抑制活性测试，这些肿瘤包括神经母细胞瘤（IMR32）、胰腺癌（CFPAC-1）、白血病（MOLT-4）、胰腺类癌（BON）和前列腺癌（PC-3）。在所有这些肿瘤细胞系中均检测到SSTR2 mRNA和蛋白质。尽管在体外实验中测得的一些效力有所丧失，但该偶联物仍显示出强大的体内抑制活性。发现JF-10-81可显著抑制这些SSTR阳性肿瘤的生长，使携带神经母细胞瘤IMR32的动物肿瘤减少87%，携带白血病MOLT-4的动物肿瘤减少97%，甚至可使CFPAC-1肿瘤消退。不幸的是，过表达SSTR的BON肿瘤在体外对CPT相对不敏感，但是，JF-10-81在体内再次显示出效力，大概是通过特异性增加肿瘤细胞内的CPT浓度，因此JF-10-81的抑制率为85%。此外，JF-10-81用于治疗高侵袭性PC-3肿瘤，皮下注射可抑制肿瘤生长（减少近60%）和肿瘤转移（超过70%）。这种偶联物通过靶向SSTR2特异性肿瘤组织展示了其广泛而出色的抗肿瘤活性，支持短肽及其类似物可作为理想的药物递送载体来改进传统化疗。
