采用裸鼠的腫瘤模型評價化合物SC263的抗前列腺癌活性
發(fā)布時間：2018-10-11 07:30
【摘要】：前列腺癌在美國和歐洲是導致男性死亡率第二高的癌癥,亞洲地區(qū)人群的患病率雖然較低但是也呈現出逐年上升的趨勢,并且其增長速度已超過了西方國家。前列腺癌的發(fā)展依賴于雄激素與其受體的結合,雄激素受體(AR)是在細胞核內行使其功能的轉錄調控因子。AR在與雄激素結合后可以被激活,促進其調控序列的轉錄從而促進癌癥的發(fā)展�，F有的前列腺癌治療方法最主要為降低患者體內雄激素的水平從而減少AR的激活,但是這種治療方法僅有短暫的療效,前列腺癌最終可以在低水平雄激素環(huán)境下繼續(xù)發(fā)展,演化為雄激素抵抗性前列腺癌(CRPC)。大多數前列腺癌死亡病例都是由雄激素抵抗性前列腺癌所導致的,雄激素抵抗性前列腺癌產生的最主要機制為癌細胞內雄激素受體AR表達量的增高,即使在雄激素水平很低的情況下仍可以維持一定量的激活的AR。因此針對雄激素抵抗性前列腺癌的藥物開發(fā)思路為設計以雄激素受體AR為靶標的藥物,達到直接抑制AR激活的目的。 由合作伙伴實驗室設計并合成的小分子化合物SC263以AR作為進攻靶標,并在體外用前列腺癌細胞株進行實驗證明了其與AR的結合能力,抑制AR激活、抑制前列腺癌細胞分裂等功能。因此該小分子化合物是否在體內也具有抑制前列腺癌發(fā)展的作用是下一步檢測其是否具有被開發(fā)為抗癌藥物前景的關鍵所在。本研究通過原代培養(yǎng)的方法獲得了成瘤性強的前列腺癌細胞,成功建立了裸鼠的前列腺癌腫瘤模型,并通過給藥實驗比較了SC263給藥組和空白對照組的腫瘤發(fā)展情況。實驗結果表明SC263在裸鼠體內可以成功與其靶標雄激素受體AR結合,抑制下游調控基因的轉錄,從而減少前列腺癌細胞的分裂、促進癌細胞的凋亡,最終表現為與對照組相比SC263給藥組的腫瘤生長更緩慢,給藥實驗結束后腫瘤最終體積和質量也較對照組小。同時,證明了SCC263在裸鼠體內的毒副作用較小,因此該小分子化合物或許安全性較高,具有被開發(fā)為新型抗雄激素抵抗性前列腺癌藥物的前景。
[Abstract]:Prostate cancer is the second leading cause of male mortality in the United States and Europe. The development of prostate cancer depends on the binding of androgen to its receptor, androgen receptor (AR), a transcriptional regulator that functions in the nucleus. AR is activated when it binds to androgen. Promote the transcription of its regulatory sequence and thus promote the development of cancer. The current treatment for prostate cancer is mainly to reduce the level of androgen in patients and thus reduce the activation of AR, but this treatment has only a temporary effect, prostate cancer can eventually continue to develop in a low level of androgen environment. Evolution into androgen resistant prostate cancer (CRPC). Androgen resistant prostate cancer is responsible for the majority of prostate cancer deaths. The most important mechanism of androgen resistant prostate cancer production is the increased expression of androgen receptor AR in cancer cells. A certain amount of activated AR. can be maintained even when androgen levels are very low Therefore, the development idea of androgen resistant prostate cancer is to design androgen receptor AR as the target drug to directly inhibit the activation of AR. The small molecular compound SC263, designed and synthesized by the partner laboratory, used AR as an attack target, and its ability to bind to AR and inhibit the activation of AR was demonstrated by using prostate cancer cell line in vitro. Inhibition of prostate cancer cell division and other functions. Therefore, whether the small molecular compound can inhibit the development of prostate cancer in vivo is the key to detect whether it has the prospect of being developed as an anticancer drug. In this study, prostate cancer cells with strong tumorigenesis were obtained by primary culture, and tumor models of prostate cancer in nude mice were successfully established, and the tumor development of SC263 group and blank control group were compared by drug administration experiment. The results showed that SC263 could successfully bind to its target androgen receptor AR in nude mice and inhibit the transcription of downstream regulatory genes, thus reducing the division of prostate cancer cells and promoting the apoptosis of cancer cells. Compared with the control group, the tumor growth of SC263 group was slower, and the final volume and mass of tumor was smaller than that of control group. At the same time, it was proved that the toxicity and side effects of SCC263 in nude mice were relatively small, so the small molecule compound might be more safe and have the prospect of being developed as a new anti-androgen resistant prostatic cancer drug.
【學位授予單位】：華中師范大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R737.25
本文編號：2263360
[Abstract]:Prostate cancer is the second leading cause of male mortality in the United States and Europe. The development of prostate cancer depends on the binding of androgen to its receptor, androgen receptor (AR), a transcriptional regulator that functions in the nucleus. AR is activated when it binds to androgen. Promote the transcription of its regulatory sequence and thus promote the development of cancer. The current treatment for prostate cancer is mainly to reduce the level of androgen in patients and thus reduce the activation of AR, but this treatment has only a temporary effect, prostate cancer can eventually continue to develop in a low level of androgen environment. Evolution into androgen resistant prostate cancer (CRPC). Androgen resistant prostate cancer is responsible for the majority of prostate cancer deaths. The most important mechanism of androgen resistant prostate cancer production is the increased expression of androgen receptor AR in cancer cells. A certain amount of activated AR. can be maintained even when androgen levels are very low Therefore, the development idea of androgen resistant prostate cancer is to design androgen receptor AR as the target drug to directly inhibit the activation of AR. The small molecular compound SC263, designed and synthesized by the partner laboratory, used AR as an attack target, and its ability to bind to AR and inhibit the activation of AR was demonstrated by using prostate cancer cell line in vitro. Inhibition of prostate cancer cell division and other functions. Therefore, whether the small molecular compound can inhibit the development of prostate cancer in vivo is the key to detect whether it has the prospect of being developed as an anticancer drug. In this study, prostate cancer cells with strong tumorigenesis were obtained by primary culture, and tumor models of prostate cancer in nude mice were successfully established, and the tumor development of SC263 group and blank control group were compared by drug administration experiment. The results showed that SC263 could successfully bind to its target androgen receptor AR in nude mice and inhibit the transcription of downstream regulatory genes, thus reducing the division of prostate cancer cells and promoting the apoptosis of cancer cells. Compared with the control group, the tumor growth of SC263 group was slower, and the final volume and mass of tumor was smaller than that of control group. At the same time, it was proved that the toxicity and side effects of SCC263 in nude mice were relatively small, so the small molecule compound might be more safe and have the prospect of being developed as a new anti-androgen resistant prostatic cancer drug.
【學位授予單位】：華中師范大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R737.25
【共引文獻】
相關期刊論文 前3條
1 張海洋;王慕文;趙勇;李連軍;陳友根;金訊波;;前列腺癌的診斷和治療現狀的探討[J];泌尿外科雜志(電子版);2013年02期
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相關碩士學位論文 前5條
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3 岳長久;血清睪酮水平、前列腺雄激素受體表達與前列腺癌臨床進展之間的研究[D];內蒙古大學;2013年
4 謝金龍;PSA升高患者坦索羅辛治療后血清PSA水平與前列腺癌活檢檢出率的研究[D];天津醫(yī)科大學;2013年
5 李曉東;新疆維吾爾族與漢族前列腺癌診斷指標的研究[D];新疆醫(yī)科大學;2013年
，本文編號：2263360
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