Kim Sunkyu, Kim Sukwon S, Bang Yung Jue, Kim Seong Jin, Lee Byeong Jae
Laboratory of Molecular Genetics, School of Biological Sciences, Seoul National University, Peptipharm Co. Ltd., Seoul 151-742, South Korea.
Peptides. 2003 Jul;24(7):945-53. doi: 10.1016/s0196-9781(03)00194-3.
In order to develop peptide agents with reduced length and enhanced tumoricidal activity, we have designed gaegurin 6 (GGN6) derivatives through deletions and/or substitutions of amino acids. The deletion of hydrophobic amino terminal region completely abolished antitumor activity whereas the deletion of carboxy terminal region had little influence on antitumor activity. Antitumor activity of the PTP peptides did not correlate with antibacterial activity. PTP7, the most potent derivative, was found to have comparable antitumor activity to GGN6 in spite of reduced number of amino acids which is about half the size of gaegurin 6; furthermore, it showed little cytotoxicity on PBMCs and RBCs. GGN6 and PTP7 also showed equivalent cytotoxicity against drug sensitive (MCF-7) and multidrug-resistant cell lines (MCF-7/DOX). Plasma membrane blebbing and DNA fragmentation of peptide-treated tumor cells indicated that the peptides could induce apoptosis in tumor cells. These results suggest that GGN6 and its derivatives can be developed as new anticancer agents and may provide a new strategy for overcoming MDR which is a major problem in cancer therapy.
为了开发长度缩短且杀瘤活性增强的肽类药物，我们通过氨基酸的缺失和/或替换设计了盖古林6（GGN6）衍生物。疏水氨基末端区域的缺失完全消除了抗肿瘤活性，而羧基末端区域的缺失对抗肿瘤活性影响很小。PTP肽的抗肿瘤活性与抗菌活性无关。尽管PTP7的氨基酸数量减少，约为盖古林6大小的一半，但它被发现具有与GGN6相当的抗肿瘤活性；此外，它对PBMC和RBC几乎没有细胞毒性。GGN6和PTP7对药物敏感细胞系（MCF-7）和多药耐药细胞系（MCF-7/DOX）也表现出同等的细胞毒性。肽处理的肿瘤细胞的质膜起泡和DNA片段化表明这些肽可诱导肿瘤细胞凋亡。这些结果表明，GGN6及其衍生物可被开发为新型抗癌药物，并可能为克服多药耐药性提供新策略，而多药耐药性是癌症治疗中的一个主要问题。
