采用裸鼠的肿瘤模型评价化合物SC263的抗前列腺癌活性

发布时间：2018-10-11 07:30

【摘要】：前列腺癌在美国和欧洲是导致男性死亡率第二高的癌症,亚洲地区人群的患病率虽然较低但是也呈现出逐年上升的趋势,并且其增长速度已超过了西方国家。前列腺癌的发展依赖于雄激素与其受体的结合,雄激素受体(AR)是在细胞核内行使其功能的转录调控因子。AR在与雄激素结合后可以被激活,促进其调控序列的转录从而促进癌症的发展。现有的前列腺癌治疗方法最主要为降低患者体内雄激素的水平从而减少AR的激活,但是这种治疗方法仅有短暂的疗效,前列腺癌最终可以在低水平雄激素环境下继续发展,演化为雄激素抵抗性前列腺癌(CRPC)。大多数前列腺癌死亡病例都是由雄激素抵抗性前列腺癌所导致的,雄激素抵抗性前列腺癌产生的最主要机制为癌细胞内雄激素受体AR表达量的增高,即使在雄激素水平很低的情况下仍可以维持一定量的激活的AR。因此针对雄激素抵抗性前列腺癌的药物开发思路为设计以雄激素受体AR为靶标的药物,达到直接抑制AR激活的目的。由合作伙伴实验室设计并合成的小分子化合物SC263以AR作为进攻靶标,并在体外用前列腺癌细胞株进行实验证明了其与AR的结合能力,抑制AR激活、抑制前列腺癌细胞分裂等功能。因此该小分子化合物是否在体内也具有抑制前列腺癌发展的作用是下一步检测其是否具有被开发为抗癌药物前景的关键所在。本研究通过原代培养的方法获得了成瘤性强的前列腺癌细胞,成功建立了裸鼠的前列腺癌肿瘤模型,并通过给药实验比较了SC263给药组和空白对照组的肿瘤发展情况。实验结果表明SC263在裸鼠体内可以成功与其靶标雄激素受体AR结合,抑制下游调控基因的转录,从而减少前列腺癌细胞的分裂、促进癌细胞的凋亡,最终表现为与对照组相比SC263给药组的肿瘤生长更缓慢,给药实验结束后肿瘤最终体积和质量也较对照组小。同时,证明了SCC263在裸鼠体内的毒副作用较小,因此该小分子化合物或许安全性较高,具有被开发为新型抗雄激素抵抗性前列腺癌药物的前景。
[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.
【学位授予单位】：华中师范大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R737.25

【共引文献】