整合素阻斷劑抗腫瘤藥物研究進(jìn)展

[摘要] 整合素是存在于細(xì)胞表面的跨膜糖蛋白受體，能介導(dǎo)細(xì)胞間的黏附，參與血管生成和腫瘤轉(zhuǎn)移，與腫瘤的發(fā)生發(fā)展密切相關(guān)。以整合素為靶點(diǎn)進(jìn)行抗腫瘤治療，可有效抑制腫瘤的生長和轉(zhuǎn)移。本文主要從抗腫瘤生長類藥物、抗腫瘤轉(zhuǎn)移類藥物、抗血管生成類藥物等方面對近年來整合素阻斷劑抗腫瘤藥物研究進(jìn)展進(jìn)行綜述，并對整合素靶向給藥的劑量問題進(jìn)行了討論。

[關(guān)鍵詞] 整合素阻斷劑；抗腫瘤；靶向；藥物

[中圖分類號] R943 [文獻(xiàn)標(biāo)識碼] A [文章編號] 2095-0616（2012）21-44-04

Development of integrin inhibitors in antitumor therapy

CHENG Tao HU Jialiang XU Hanmei

College of Life Science and Technology， China Pharmaceutical University， Nanjing 210009， China

[Abstract] Integrins are transmembrane glycoprotein receptor on cell surface， which can mediate adhesion between cells and involve in angiogenesis and tumor metastasis. Therefore， integrins are closely related with tumorigenesis and tumor development. Integrin-targeted anti-tumor therapy could effectively inhibit tumor growth and metastasis. This review mainly focused on development of integrin inhibitors in anti-tumor therapy in recent years from aspects of anti-tunor growth， anti-tumor metastasis， anti-angiogenesis and so on. Further more， dual function of doses in integrin-targeted therapy are also discussed.

[Key words] Integrin inhibitor；Anti-tumor；Targeted； Drug

整合素作為黏附分子，可以調(diào)節(jié)細(xì)胞-細(xì)胞、細(xì)胞-細(xì)胞外基質(zhì)（extracellular matrix，ECM）間的黏附。整合素所介導(dǎo)的腫瘤細(xì)胞與腫瘤細(xì)胞、血管內(nèi)皮細(xì)胞及ECM之間的相互作用影響腫瘤的發(fā)生、增殖、侵襲和轉(zhuǎn)移到其他組織的能力。

惡性轉(zhuǎn)化是腫瘤發(fā)生的初始步驟。細(xì)胞發(fā)生惡變時，細(xì)胞表面的整合素發(fā)生構(gòu)型或表達(dá)水平的改變，從而調(diào)節(jié)細(xì)胞內(nèi)外的信號轉(zhuǎn)導(dǎo)，進(jìn)而影響細(xì)胞之間、細(xì)胞與ECM間的相互作用，并最終影響腫瘤細(xì)胞的生長、存活、分化及凋亡。原位增殖是腫瘤發(fā)展的前提條件。Fawzi Aoudjit等[1]發(fā)現(xiàn)，整合素通過與ECM作用激活胞內(nèi)多條信號通路，促進(jìn)腫瘤細(xì)胞的增殖，并引起化療耐藥性。腫瘤細(xì)胞從原發(fā)部位脫落、遷移至遠(yuǎn)部位的靶器官，整合素也起了不可忽略的作用。研究表明[2]：整合素使腫瘤細(xì)胞同質(zhì)性黏附下降，異質(zhì)性黏附增加。ECM是腫瘤侵襲的屏障，整合素可與MMP結(jié)合并正向調(diào)控MMP的表達(dá)，直接破壞和降解ECM，從而為腫瘤細(xì)胞的轉(zhuǎn)移做充分準(zhǔn)備。……