近期出版的国际知名学术刊物《肿瘤研究》， 在世界上首次报道了由北京大学顾军、中国科学院高锦课题组合作完成的成果——具有抗肿瘤作用的双靶点基因工程多肽及其药理活性特点。
肿瘤严重危害人类健康，其发病和无毒有效治疗的需求呈急剧增长趋势。由于肿瘤是多阶段形成的复杂性疾病，单一靶向的治疗或单一靶点的药物的疗效都不理想，因此，整合治疗成为公认的最佳肿瘤治疗手段。在肿瘤的药物治疗方面，组合用药已是常规临床治疗模式，但单分子多靶点安全有效治疗肿瘤的药物鲜为人知。
本期《肿瘤研究》的报道指出，双靶点抗肿瘤基因工程多肽可作为肿瘤生长过程中发挥重要作用的基质金属蛋白酶和血管内皮细胞二者的抑制剂，显示了新多肽具有防止肿瘤新生血管生成的作用，不仅整体无放疗、化疗所致的毒副作用，而且具有很好的抑制肿瘤生长和转移等的治疗作用。
目前尽管以基质金属蛋白酶和内皮细胞这两个因素为靶点的药物不断问世，其中不乏基因工程药物，但中国科学家通过克服一个又一个技术难关，巧妙地将作用于基质金属蛋白酶小肽序列和作用于内皮细胞的多肽序列融合在一起，并利用基因工程的方法率先在国内表达和纯化了该物质，获得一个双靶点的融合多肽类。通过对该多肽系统的生物学和药学研究，从分子、细胞及动物模型水平证明了其可有效作用于这两个靶点，通过抑制基质蛋白酶的活性及内皮细胞的增殖和迁移阻止肿瘤新生血管的形成，从而有效抑制肿瘤生长和转移，其效果优于单一靶点多肽作用。因而，更加显示了这一融合多肽优越性的防治肿瘤的生物学特性，一旦新药研发过程全部完成上市，有望为肿瘤患者带来更大福音。
该研究首次提出并实现了抗肿瘤多靶点基因工程多肽药物的设计思路和技术路线，为创制基因工程药物提供了新思路，因而受到国际同行关注。（科学时报）
原始出处：
Cancer Research 67, 7295-7300, August 1, 2007. doi: 10.1158/0008-5472.CAN-06-3920
Experimental Therapeutics, Molecular Targets, and Chemical Biology
Targeting Matrix Metalloproteinases and Endothelial Cells with a Fusion Peptide against Tumor
Yufei Zou1, Yahui Chen1, Yongqiang Jiang1,3, Jin Gao2 and Jun Gu1
1 National Key Laboratory of Protein Engineering and Plant Gene Engineering, College of Life Sciences, Peking University; 2 Molecular Pharmacy Division, Institution of Biophysics, Chinese Academy of Sciences; and 3 Academy of Military Medical Sciences, Beijing, China
Requests for reprints: Jun Gu, Department of Biochemistry and Molecular Biology, College of Life Sciences, Peking University, Beijing 100871, P.R. China. Phone: 86-10-62759940; Fax: 86-10-62756174; E-mail: gj@pku.edu.cn .
Development of novel therapy for patients with tumor is still a challenge at the present time. We designed a fusion peptide (RK5) with two targets as a novel agent against tumor. The fusion peptide RK5 containing the kringle 5 fragment of human plasminogen and a decapeptide (CTTHWGFTLC) was constructed and expressed in yeast. Matrix metalloproteinase (MMP) activity, proliferation, and migration of endothelial cells were examined in vitro, respectively. Angiogenesis, tumor growth, metastasis, and survival time were evaluated in in vivo models. Administration of RK5 was delivered by both protein and gene approach. The results showed that RK5 inhibited the activity of MMP-9 and exhibited more inhibitory effects on proliferation and migration of endothelial cells than that of kringle 5 fragment and decapeptide individually. RK5 also inhibited angiogenesis, tumor growth, and metastasis and increased survival time of mice bearing tumor. In addition, the effectiveness of RK5 could be achieved by both protein and gene delivery. In conclusion, RK5 has potential to inhibit tumor growth and metastasis and to prolong survival time of animals bearing tumor. Therefore, fusion peptide RK5 with two targets provides a new design for the development of antitumor drugs and has potential for clinical application. [Cancer Res 2007;67(15):7295–300]
