Rege Kaushal, Patel Suraj J, Megeed Zaki, Yarmush Martin L
The Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Shriners Hospital for Children, Boston, Massachusetts 02114, USA.
Cancer Res. 2007 Jul 1;67(13):6368-75. doi: 10.1158/0008-5472.CAN-06-3658.
We describe the design, generation, and in vitro evaluation of targeted amphipathic fusion peptides and immunoconjugates for the ablation of prostate cancer cells. The overexpression of the prostate-specific membrane antigen (PSMA) was exploited as means to specifically deliver cytotoxic peptides to prostate cancer cells. Cationic amphipathic lytic peptides were chosen as cytotoxic agents due to their ability to depolarize mitochondrial membranes and induce apoptosis. Specific delivery of the lytic peptide was facilitated by PSMA-targeting peptides and antibodies. Our results indicate that although the use of PSMA-targeted peptides only modestly enhanced the cytotoxic activity of the lytic peptide, peptide-antibody conjugates were two orders of magnitude more potent than untargeted peptide. In addition to quantifying the cytotoxic activities of the individual constructs, we also investigated the mechanisms of cell death induced by the fusion peptides and immunoconjugates. Although fusion peptides induced oncotic/necrotic death in cells, treatment with immunoconjugates resulted in apoptotic death. In summary, immunoconjugates based on lytic peptides are a promising class of therapeutics for prostate cancer therapy and warrant further investigation.
我们描述了用于前列腺癌细胞消融的靶向两亲性融合肽和免疫缀合物的设计、生成及体外评估。利用前列腺特异性膜抗原（PSMA）的过表达作为将细胞毒性肽特异性递送至前列腺癌细胞的手段。阳离子两亲性溶细胞肽因其能够使线粒体膜去极化并诱导细胞凋亡而被选作细胞毒性剂。PSMA靶向肽和抗体促进了溶细胞肽的特异性递送。我们的结果表明，尽管使用PSMA靶向肽仅适度增强了溶细胞肽的细胞毒性活性，但肽 - 抗体缀合物的效力比非靶向肽高两个数量级。除了量化各个构建体的细胞毒性活性外，我们还研究了融合肽和免疫缀合物诱导细胞死亡的机制。尽管融合肽在细胞中诱导了胀亡/坏死性死亡，但免疫缀合物处理导致了凋亡性死亡。总之，基于溶细胞肽的免疫缀合物是一类有前景的前列腺癌治疗药物，值得进一步研究。
