近期出版的國際知名學術(shù)刊物《腫瘤研究》,， 在世界上首次報道了由北京大學顧軍、中國科學院高錦課題組合作完成的成果——具有抗腫瘤作用的雙靶點基因工程多肽及其藥理活性特點,。
腫瘤嚴重危害人類健康，其發(fā)病和無毒有效治療的需求呈急劇增長趨勢。由于腫瘤是多階段形成的復雜性疾病,，單一靶向的治療或單一靶點的藥物的療效都不理想，因此,，整合治療成為公認的最佳腫瘤治療手段,。在腫瘤的藥物治療方面，組合用藥已是常規(guī)臨床治療模式,，但單分子多靶點安全有效治療腫瘤的藥物鮮為人知,。
本期《腫瘤研究》的報道指出，雙靶點抗腫瘤基因工程多肽可作為腫瘤生長過程中發(fā)揮重要作用的基質(zhì)金屬蛋白酶和血管內(nèi)皮細胞二者的抑制劑,，顯示了新多肽具有防止腫瘤新生血管生成的作用,，不僅整體無放療、化療所致的毒副作用,，而且具有很好的抑制腫瘤生長和轉(zhuǎn)移等的治療作用,。
目前盡管以基質(zhì)金屬蛋白酶和內(nèi)皮細胞這兩個因素為靶點的藥物不斷問世，其中不乏基因工程藥物,，但中國科學家通過克服一個又一個技術(shù)難關(guān),，巧妙地將作用于基質(zhì)金屬蛋白酶小肽序列和作用于內(nèi)皮細胞的多肽序列融合在一起，并利用基因工程的方法率先在國內(nèi)表達和純化了該物質(zhì),，獲得一個雙靶點的融合多肽類,。通過對該多肽系統(tǒng)的生物學和藥學研究，從分子,、細胞及動物模型水平證明了其可有效作用于這兩個靶點,，通過抑制基質(zhì)蛋白酶的活性及內(nèi)皮細胞的增殖和遷移阻止腫瘤新生血管的形成，從而有效抑制腫瘤生長和轉(zhuǎn)移,，其效果優(yōu)于單一靶點多肽作用,。因而，更加顯示了這一融合多肽優(yōu)越性的防治腫瘤的生物學特性,，一旦新藥研發(fā)過程全部完成上市,，有望為腫瘤患者帶來更大福音。
該研究首次提出并實現(xiàn)了抗腫瘤多靶點基因工程多肽藥物的設(shè)計思路和技術(shù)路線,，為創(chuàng)制基因工程藥物提供了新思路,，因而受到國際同行關(guān)注。（科學時報）
原始出處：
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: [email protected] .
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]
