药物治疗激素抵抗型前列腺癌机制研究

对于晚期前列腺癌,一般给予雄激素剥夺疗法.去势治疗后2~3年的时间几乎所有的肿瘤都转化为雄激素抵抗性前列腺癌.紫杉醇类药物是目前近年来治疗激素抵抗性前列腺癌的一种有效的化疗药物,其能减轻患者疼痛,延长患者寿命.随着近年来科技水平的发展,越来越多的药物进入临床中造福于晚期前列腺癌患者.本文主要针对紫杉醇治疗激素抵抗性前列腺癌及新兴的抗前列腺癌药物作用机制进行综述.     

前列腺癌的药物治疗

前列腺癌分为激素依赖型和激素非依赖型,前者对雄激素敏感,去除雄激素后细胞发生凋亡;而后者对去除雄激素无反应,发生转移后对常规肿瘤化疗药物治疗不敏感,死亡率高。对于不同类型的前列腺癌,常采用不同的药物进行治疗。     

前列腺癌内分泌治疗药Degarelix

目前前列腺癌治疗药物主要包括抗雄激素类、芳香化酶抑制剂、雌激素类、孕酮类、促性腺激素释放激素（GnRH）类似物以及若干常规抗有丝分裂的化疗药物（如雌莫司汀磷酸钠、盐酸米托蒽醌和多西紫杉醇）,其中GnRH类似物备受关注,作为一种激素疗法,其可致睾酮减少至去势水平,从而控制前列腺癌的生长和扩散。     

前列腺癌治疗药物的研究新进展*

目前临床上对前列腺癌的治疗方法包括手术治疗、放射治疗、内分泌治疗、化学治疗及免疫治疗等,其中内分泌治疗是晚期前列腺癌治疗的主要手段。以雄激素受体阻滞剂为代表的各类新型抗前列腺癌药物的开发正在受到广泛关注。现对近年来前列腺癌治疗药物的研究进展,包括目前尚处于临床试验阶段的一些药物先导化合物进行综述,为相关领域的科研人员提供参考。     

抗肿瘤药——Novacea公司的三种抗肿瘤药物

美国Novacea生物技术公司一直致力于癌症的治疗，它拥有三种可用于临床的药物。其首选候选药物为DN-101（I），用于治疗雄激素非依赖性前列腺癌（又称激素治疗无效的前列腺癌），已进入Ⅲ期临床试验阶段。试验主要将（I）作为前列腺癌的标准治疗药物Taxotere（docetaxel，多西他赛）的添加用药。Novacea公司于2002年7月从匹兹堡大学获得（I）的专有权。     

前列腺癌患者血皮质醇胆固醇变化及其意义

目的 探讨前列腺癌雄激素非依赖发生的机制.方法 根据临床疗效及PSA变化将前列腺癌(PCa)患者分为激素依赖和激素非依赖两组,分别应用放射免疫法和标准酶法检测血皮质醇和总胆固醇(TC)水平,并与前列腺增生(BPH)患者相对比.结果 血皮质醇水平PCa患者明显高于BPH患者(P<0.01),雄激素非依赖者明显高于雄激素依赖者(P<0.05).总胆固醇水平PCa高于BPH(P<0.05),均高于正常值,激素依赖和非依赖之间无明显差别.结论 胆固醇是前列腺癌的促发因素,皮质醇与前列腺癌激素非依赖的发生有密切关系.     

三个抗前列腺癌药物的研制

<正>1前言1.1前列腺癌与雄激素前列腺癌的发生和增殖与雄激素的刺激作用密切相关,阻断雄激素作用是防治前列腺癌的生物学基础。手术去势可很大程度上切断雄激素来源,但并不彻底,因为肾脏也可合成雄激素。药物治疗的原则是抑制雄激素的生成,或阻断雄激素受体功能的拮抗剂。甾体类抗雄激素治疗,如醋酸环丙孕酮(cyproterone acetate)有孕激素和促性腺激素作用等不良反应,     

非雄激素竞争型雄激素受体拮抗剂设计策略

雄激素受体(androgen receptor,AR)是前列腺癌治疗中最为重要的药物靶点,但抗雄激素药物在使用过程中产生的耐药性问题给前列腺癌患者的治疗带来了巨大挑战.本文回顾了雄激素受体的结构功能及传统治疗位点产生药物抗性的原因,并总结非雄激素竞争型的雄激素受体拮抗剂设计策略,为发展新型抗前列腺癌药物提供依据.     

比卡鲁胺治疗前列腺癌的临床应用

比卡鲁胺是一种新型的非甾体抗雄激素药物,内分泌治疗是前列腺癌治疗的主要手段。本文就比卡鲁胺单药治疗前列腺癌、联合化疗治疗前列腺癌及联合放疗或去势手术治疗前列腺癌的临床疗效作一综述。     

促进骨合成代谢药物的研究进展

目前治疗骨质疏松症的药物分为以抑制骨分解代谢为主和以促进骨合成代谢为主的两大类。笔者综述了促进骨合成代谢药物的研究进展,包括氟化物、甲状旁腺激素及甲状腺旁激素相关肽、锶制剂、生长激素与胰岛素样生长因子、他汀类、瘦素、雄激素、环孢素A、高选择性EP4受体激动剂、中药等等。     

作用于雄激素受体不同结合位点的前列腺癌治疗药物的研究进展

前列腺癌是最常见的男性泌尿生殖系统的恶性肿瘤。雄激素受体在前列腺癌的发生、发展中起着重要作用。目前,所有治疗前列腺癌的药物(包括第一代的氟他胺、比卡鲁胺、尼鲁米特和第二代的恩扎鲁胺)都与雄激素受体的配体结合口袋结合,并且这些药物有着相似的分子结构,这可能引起药物之间的交叉耐药。为了避免耐药性的产生,研究者们致力于发现雄激素受体上新的药物结合位点。除雄激素受体配体结合位点外,主要对作用于氮端结合位点上的第一活性功能区(AF1)、第二活性功能区(AF2)、AF2附近的第三结合功能区(BF3)和DNA结合位点(DBD)的药物进行综述。     

Non-steroidal anti-androgens in prostate cancer - current treatment practice

Adenocarcinoma of the prostate is a common disease that causes significant morbidity and mortality in the adult male population. Hormonal therapy for prostate cancer is considered when a patient fails with initial curative therapy, such as radical prostatectomy or definitive radiation therapy, or if he is found with an advanced disease. Many hormonal agents have been developed to exploit the fact that prostate cancer growth is dependent on androgen. Non-steroidal anti-androgens (NSAAs) block androgen at the cellular level. Numerous clinical trials comparing monotherapy of castration and combination therapy of castration and NSAAs have been performed. At present, the results of the trials with regard to the survival of patients under therapy are conflicting. When the disease recurs in a patient in the middle of combination androgen blockade therapy, androgen withdrawal should be considered. The benefits of NSAA in monotherapy, intermittent or neoadjuvant therapy are not clear at present. Better designed, larger cohort clinical trial may be necessary to clarify the confusion.     

Non-steroidal anti-androgens in prostate cancer--current treatment practice

Adenocarcinoma of the prostate is a common disease that causes significant morbidity and mortality in the adult male population. Hormonal therapy for prostate cancer is considered when a patient fails with initial curative therapy, such as radical prostatectomy or definitive radiation therapy, or if he is found with an advanced disease. Many hormonal agents have been developed to exploit the fact that prostate cancer growth is dependent on androgen. Non-steroidal anti-androgens (NSAAs) block androgen at the cellular level. Numerous clinical trials comparing monotherapy of castration and combination therapy of castration and NSAAs have been performed. At present, the results of the trials with regard to the survival of patients under therapy are conflicting. When the disease recurs in a patient in the middle of combination androgen blockade therapy, androgen withdrawal should be considered. The benefits of NSAA in monotherapy, intermittent or neoadjuvant therapy are not clear at present. Better designed, larger cohort clinical trial may be necessary to clarify the confusion.     

β2 微球蛋白在内分泌治疗前列腺癌根治术后患者体内表达与预后关系研究

目的观察β2微球蛋白在内分泌治疗前列腺癌根治术后患者体内表达情况及其与患者预后关系。方法选取我院行前列腺根治术联合内分泌治疗病例30例,术后3周服用氟他胺（250mg,3次/天）。分别在治疗前、治疗后3月、6月、12月收集患者血清,采用放射免疫法检测血清β2微球蛋白的表达。分析患者β2微球蛋白表达水平与患者Gleason评分以及PSA的关系。结果治疗后β2微球蛋白以及PSA水平均显著降低,差异有统计学意义（P〈0.05）。Pearson相关性分析显示,β2微球蛋白以及PSA水平有相关性（r1=0.693,r2=0.627,P〈0.05）,Gleason评分与β2微球蛋白以及PSA表达水平呈正相关（r=0.857,P〈0.05;r=0.793,P〈0.05）。结论血清β2微球蛋白是诊断以及检测肿瘤治疗预后的有效指标,与PSA协同观察可以提高临床诊断以及治疗水平。     

Current drug therapy for prostate cancer: an overview

Prostate cancer is the most common cancer amongst men in the USA and the second most common malignant cause of male death worldwide after lung cancer. The life time risk of having microscopic evidence of prostate cancer for a 50 year old man is 42%. Prostate cancer is thus becoming an increasingly significant global health problem in terms of mortality, morbidity, as well as economically. This review, discusses current medical therapeutic options for prostate cancer including traditional treatments using luteinising hormone releasing analogues (LHRH), anti-androgens and estrogen treatments, and the use of novel drugs directed against molecular targets considered important in oncogenesis and metastasis. Prostate cancer chemoprevention using 5alpha-reductase inhibitors and the role of gene therapy are also considered.     

Abarelix: the first gonadotrophin-releasing hormone antagonist for the treatment of prostate cancer

The high incidence of prostate cancer makes it a major healthcare problem and the second leading cancer-related cause of death among men in developed countries. The hormonal treatment of prostate cancer is indicated for the palliation of symptomatic and metastatic disease in older patients, and as neoadjuvant treatment of different modalities of radiotherapy. This hormonal treatment is based on the study conducted by Huggins in 1940 and consists of androgen suppression. Since the clinical availability of the first luteinising hormone-releasing hormone (LHRH) agonist, no significant improvement has been made in the field of medical castration. Taking these data into consideration, the recent approval of abarelix by the FDA, the first gonadotrophin-releasing hormone (GnRH) antagonist, appears to be promising news. The pharmacology of the molecule and the clinical studies that led to FDA approval will be reviewed. The place of GnRH antagonists in the treatment modalities of prostate cancer will then be discussed.     

Abarelix: the first gonadotrophin-releasing hormone antagonist for the treatment of prostate cancer

The high incidence of prostate cancer makes it a major healthcare problem and the second leading cancer-related cause of death among men in developed countries. The hormonal treatment of prostate cancer is indicated for the palliation of symptomatic and metastatic disease in older patients, and as neoadjuvant treatment of different modalities of radiotherapy. This hormonal treatment is based on the study conducted by Huggins in 1940 and consists of androgen suppression. Since the clinical availability of the first luteinising hormone-releasing hormone (LHRH) agonist, no significant improvement has been made in the field of medical castration. Taking these data into consideration, the recent approval of abarelix by the FDA, the first gonadotrophin-releasing hormone (GnRH) antagonist, appears to be promising news. The pharmacology of the molecule and the clinical studies that led to FDA approval will be reviewed. The place of GnRH antagonists in the treatment modalities of prostate cancer will then be discussed.     

ADH1, an N-cadherin inhibitor, evaluated in preclinical models of angiogenesis and androgen-independent prostate cancer

The conversion from E-cadherin to N-cadherin has been observed in several human cancer types, including prostate cancer, with more homogenous expression of N-cadherin detected in high-grade prostate tumors. N-cadherin, in vitro, has been shown to promote cell mobility, migration and invasion of several cancer cell lines, indicating the possibility of N-cadherin as a molecular target of cancer therapy. Herein, we examined the potential of an N-cadherin inhibitor, ADH1, in reducing tumor angiogenesis ex vivo and delaying tumor progression in vivo. Our data demonstrate that ADH1, at the dosages evaluated, does not display either antiangiogenic activity in a rat aortic ring assay or antitumor potential in a PC3 subcutaneous xenograft tumor model. We detected cytotoxic activity in human umbilical vein endothelial cells, PC3, and Tsu-Pr1 cells, when ADH1 exposure was evaluated at 500 micromol/l or above.     

Combination therapy using LHRH and somatostatin analogues plus dexamethasone in androgen ablation refractory prostate cancer patients with bone involvement: a bench to bedside approach

The development of resistance to anticancer therapies is a major hurdle in preventing long-lasting clinical responses to conventional therapies in hormone-refractory prostate cancer. Herein, the molecular evidence documenting that bone metastasis microenvironment survival factors (mainly the paracrine growth hormone-independent, urokinase-type plasminogen activator-mediated increase of IGF-1 and the endocrine production of growth hormone-dependent IGF-1, mainly liver-derived IGF-1 production) produce an epigenetic form of prostate cancer cells that are resistant to proapoptotic therapies is reviewed. Consequently, the authors present the conceptual framework of a novel antibone microenvironment survival factor, mainly an anti-IGF-1 hormonal manipulation for androgen ablation refractory prostate cancer (a combination of conventional androgen ablation therapy [luteinising hormone-releasing hormone agonist-A or orchiectomy]) with dexamethasone plus somatostatin analogue, which yielded durable objective responses and major improvement of bone pain and performance status in stage D3 prostate cancer patients.     

Synergistic cytotoxic interaction in hormone-refractory prostate cancer with the triple combination docetaxel-erlotinib and 5-fluoro-5'-deoxyuridine

The current reference treatment of hormone-refractory prostate cancer consists mainly of chemotherapy with docetaxel. To improve the management of advanced prostate cancer, one should examine the benefits of adding other agents to docetaxel. We examined the growth inhibitory effects of a triple combination, including the anti-epidermal growth factor receptor drug erlotinib, docetaxel and 5-fluoro-5'-deoxyuridine (the main intermediary metabolite of capecitabine), on the human prostate cancer cell lines PC3 and DU145, which are both devoid of androgen receptors. Marked synergistic cytotoxic effects were observed with the application of the double combination of erlotinib-5-fluoro-5'-deoxyuridine for both cell lines and to a lesser magnitude with the triple combination. For PC3 cells, all conditions resulted in synergistic interactions. The combination between erlotinib and docetaxel resulted in an approximately 50% reduction in thymidylate synthase activity (the molecular target of 5-fluorodeoxyuridine monophosphate, the active capecitabine anabolite) with an higher impact observed with DU145 cells than with PC3 cells. Neither erlotinib nor docetaxel alone displayed marked effects on thymidine phosphorylase activity (the enzyme that governs at the cellular level the final and crucial step in the activation cascade of capecitabine), in contrast to their combination that resulted in a strong increase in thymidine phosphorylase activity in PC3 cells. These data may serve as a rational basis for setting up clinical trials in advanced prostate cancer combining epidermal growth factor receptor-targeting agents like erlotinib together with docetaxel and capecitabine.