sTRAIL对多种肿瘤细胞显示超强选择性杀伤活性,但临床应用仅对部分肿瘤有确切治疗效果。sTRAIL主要激活TRAIL R1诱导细胞凋亡，多数肿瘤高表达TRAIL R2而对其产生抗性。融合肿瘤细胞特异性识别分子，可提高sTRAIL激活TRAIL R2的能力而增强其抗肿瘤作用。申请人前期选择高亲和力、高选择性、不含半胱氨酸的天然肿瘤导向肽蛙皮素与sTRAIL融合，显著增强了sTRAIL对肿瘤细胞，尤其是抗性肿瘤细胞的结合和杀伤能力。本项目拟进一步研究利用蛙皮素等天然肿瘤导向肽与sTRAIL构建的融合蛋白，确定其对抗性肿瘤细胞杀伤活性的增强作用及机制，单独或与药物联用体内抗肿瘤效果，评价将其开发为新型抗肿瘤药物的可能性。项目选择的天然肿瘤导向肽具有分子小、亲和力强、不含半胱氨酸等优点，将其与sTRAIL融合，可望推出系列自主知识产权，高选择性、无或低毒性的抗肿瘤蛋白，为肿瘤靶向治疗提供新选择。

Soluble tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) is cytotoxic in a varitey of tumor cells, but non-toxic in normal cells. Due to the high selectivity, sTRAIL is attractive in being developed as novel anti-tumor drugs. However, sTRAIL is only promising in clinical therapy for partial types of tumors. In fact, sTRAIL induce apoptosis in tumor cells mainly through the pathway mediated by the death receptor TRAIL R1. In addition, sTRAIL had low affinity for another death receptor TRAIL R2. Therefor, neumorious tumor cells evolved resistance to sTRAIL by prompted expression of TRAIL R2. This resistance might be overcomed by fusion sTRAIL to a ligand recongizing specific molecule on tumor cells, which resulted in improvement of the affinity of sTRAIL for TRAIL R2. In previous works performed by the applicant, many chimeric proteins had been constructed by fusion sTRAIL to bombesin, a natural tumor-homing peptide with high affinity for bombesin receptor that widely expressed on tumor cells but not normal cells. The chimeric protein showed much higher cytotoxicity in tumor cells, expecially in sTRAIL-resistant tumor cells, than that of sTRAIL. It indicates that the cytotoxicity of sTRAIL was significantly enhanced by fusion to the tumor-homing peptide bombesin. In this project, chimeric proteins consists of sTRAIL and bombesin will be further characterized in cytotoxicity in a wide variety of tumor cells, the binding ability to TRAIL receptors, the relationship between cell binding and cytotoxicity, the mechianism of chimiric protein-induced apoptosis, in vivo anti-tumor effect when it was used as a single agent as well as combined with other agents. The possibility of developing these chimeric proteins as novel anti-tumor drugs will be evaluated in this project. Taking the advantages of small molecule, high affinity for receptor and lacking Cystine amino acid in molecule, the natural tumor-homing peptide bombesin is probably more promising than other molecules described in previous works in improvement of cytotoxicity of sTRAIL in tumor cells. And the chimeric proteins containing bombesin and sTRAIL might be developed as novel drugs that is alternative for cancer tagerted biotherapy.