【作者】 高庆贞；

【导师】 吕家驹；

【作者基本信息】 山东大学 ， 外科学， 2006， 博士

【摘要】 研究背景：前列腺癌是常见的男性泌尿生殖系肿瘤，在我国人群中的发病率有逐渐增长的趋势。对大多数前列腺癌患者，雄激素阻断治疗能取得良好效果。但在治疗的过程中，肿瘤通过选择机制和细胞自身的变化，使癌细胞获得更高的增殖活性，最终导致雄激素阻断治疗的失败。目前对晚期前列腺癌缺乏有效的治疗手段。糖皮质激素是肾上腺分泌的甾体类激素，在对肿瘤的治疗中，常应用糖皮质激素类药物减轻化疗药物的毒性反应，同时保护健康细胞免遭基因毒性药物的损伤。人们很早就注意到糖皮质激素类药物能改善前列腺癌患者的一般状况。近来发现，使用糖皮质激素类药物能降低晚期前列腺癌患者的前列腺特异性抗原(PSA)水平，提示糖皮质激素可能具有抑制前列腺癌细胞增殖的作用。目前对这种作用机制方面的研究不多。细胞外信号调节激酶(ERK1／2)通路是细胞内重要的信号传导通路，多数生长因子通过此通路促进细胞的增殖和分化，多种药物通过抑制ERK1／2通路的活性(即ERK1／2的磷酸化反应)发挥抗肿瘤作用。为了探讨糖皮质激素对前列腺癌的作用机制，我们研究了合成的糖皮质激素类药物地塞米松对前列腺癌细胞ERK1／2信号通路活性的影响。 实验分两部分。第一部分，比较前列腺癌LNCaP、PC-3和DU145细胞的增殖活性以及细胞内ERK1／2信号通路活化程度的差别，并研究激活和阻断ERK1／2信号通路后细胞增殖活性的变化。通过这些研究，明确前列腺癌细胞ERK1／2信号通路的活化状态以及ERK1／2信号通路对前列腺癌细胞增殖的意义。第二部分，更多还原

【Abstract】 Background: Prostate cancer is a common noncutaneous cancer in men. The incidence of this disease is increasing in recent years in Chinese people. When prostate cancers first occur, they are dependent on androgens for growth and can be treated successfully with androgen ablation therapy. However, after prolonged antiandrogen therapy for about 3 years, the cancer eventually acquires the ability to proliferate and refractory to hormonal therapy. Few therapies have been proven definitively to prolong survival of patients with hormone refractory prostate cancer. Glucocorticoids are regulatory molecules that control metabolism, development, inflammation, cell growth, proliferation, and differentiation. Before, during, and after chemotherapy of cancers, glucocorticoids are given to reduce acute toxicity, particularly hyperemesis, and to protect normal tissue of cancer patients against the long-term effects of genotoxic drugs. Moreover, glucocorticoids have direct antitumor effects and are used in the therapeutic induction of apoptotic cell death in malignant lymphoid cells. For solid tumors such as lung cancer, breast cancer, hepatomas, glucocorticoids can also suppress cancer cell proliferation and induce cell differentiation. Glucocorticoids have been used in the treatment of advanced prostate cancer due to their overall palliative effect. Several recent studies of glucocorticoids therapy shew serum prostate-specific antigen levels declined more than 50% in 20%—61% of patients with hormone refractory prostate cancer. This indicates更多还原