【摘要】：紫杉醇是廣譜抗腫瘤藥物,其獨特的抗癌機(jī)理,在臨床上相繼被證明對卵巢癌、子宮癌、乳腺癌等多種癌癥具有較明顯的治療成果,它主要作用于微管蛋白,可以加強(qiáng)微管蛋白聚合,并且阻止其解聚,使細(xì)胞的有絲分裂過程受阻,進(jìn)而導(dǎo)致細(xì)胞凋亡,目前在臨床上已作為一線用藥治療乳腺癌、卵巢癌和非小細(xì)胞肺癌。然而,紫杉醇存在著一定的缺陷,如溶解度和選擇性較差,毒副作用較大,使用不方便,易產(chǎn)生耐藥性及無法透過血腦屏障等。針對這些問題,研究者從紫杉醇的化學(xué)結(jié)構(gòu)、構(gòu)效關(guān)系以及制劑等角度著手研究,研制了一些療效顯著的紫杉醇類似物的新結(jié)構(gòu)及新劑型。本實驗是探究不同濃度下的紫杉醇的衍生物(TM-2)對多種腫瘤細(xì)胞的抑制作用,及可能作用機(jī)制。通過體外細(xì)胞培養(yǎng),應(yīng)用MTT、CCK-8法檢測對觀察TM-2對人源性腫瘤細(xì)胞人前列腺癌(PC-3)細(xì)胞、人卵巢癌(SK-OV-3,A2780)細(xì)胞、人宮頸癌(He La)細(xì)胞、人乳腺癌(MCF-7)細(xì)胞、人結(jié)直腸癌(HCT-116)細(xì)胞、人肝癌(Hep G2)細(xì)胞、人胰腺癌(Bx PC-3)細(xì)胞、人肺腺癌(A549)細(xì)胞的增殖抑制作用,應(yīng)用Annexin V-FITC/PI雙染、流式細(xì)胞術(shù)、Western Blot檢測TM-2誘導(dǎo)腫瘤細(xì)胞凋亡的作用及機(jī)制。結(jié)果表明TM-2在體外可以明顯抑制多種人源性腫瘤細(xì)胞的增殖,其作用可能與其激活線粒體和死亡受體途徑,上調(diào)Bax蛋白表達(dá),下調(diào)Bcl-2蛋白表達(dá),降低線粒體膜電位,促進(jìn)caspase-3的剪切活化誘導(dǎo)細(xì)胞凋亡有關(guān)。
[Abstract]:Paclitaxel is a broad-spectrum antineoplastic drug with its unique anticancer mechanism, which has been proved to be effective in the treatment of ovarian cancer, uterine cancer, breast cancer and many other cancers. It mainly acts on tubulin. It can enhance tubulin polymerization and prevent it from deaggregating, thus blocking the mitotic process of cells and leading to apoptosis. It has been used as a first-line drug in the treatment of breast cancer, ovarian cancer and non-small cell lung cancer. However, paclitaxel has some defects, such as poor solubility and selectivity, large toxic side effects, inconvenient use, resistance to drug resistance and inability to penetrate the blood-brain barrier. In order to solve these problems, the researchers studied the chemical structure, structure-activity relationship and preparation of paclitaxel, and developed some new structures and formulations of taxol analogues. The aim of this study was to investigate the inhibitory effect of taxol derivatives (TM-2) on various tumor cells and its possible mechanism. Human prostate cancer (PC-3) cells, human ovarian cancer (SK-OV-3,A2780) cells and human cervical cancer (He La) cells were detected by MTT,CCK-8 assay in vitro. The proliferation inhibition of human breast cancer (MCF-7) cells, human colorectal cancer (HCT-116) cells, human hepatocellular carcinoma (Hep G2) cells, human pancreatic cancer (Bx PC-3) cells and human lung adenocarcinoma (A549) cells were detected by Annexin V-FITC/PI double staining. Flow cytometry (FCM), Western Blot was used to detect the apoptosis of tumor cells induced by TM-2. The results showed that TM-2 could significantly inhibit the proliferation of human tumor cells in vitro, which might be related to its activation of mitochondria and death receptor pathway, up-regulation of Bax protein expression, down-regulation of Bcl-2 protein expression, and reduction of mitochondrial membrane potential. Promoting shear activation of caspase-3 induces apoptosis.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R96

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