抑制雄激素代谢和新生:去势抵抗型前列腺癌治疗的新靶点

前列腺癌(PCa)经雄激素剥夺治疗后终将进展为临床难治的去势抵抗型前列腺癌(CRPC),其重要的机制之一就是人体内雄激素代谢途径的改变以及CRPC细胞内雄激素的新生使得PCa能够有效对抗去势后睾丸来源雄激素的大幅度减少。当前,针对雄激素代谢与新生过程中的关键酶开发新一代的靶向抑制剂已成为热点,为更有效地治疗CRPC提供了新的方法和手段。     

去势抵抗型前列腺癌雄激素代谢及新生的研究进展

前列腺癌(PCa)经雄激素剥夺治疗(ADT)后普遍进展为去势抵抗型前列腺癌(CRPC),其可能的机制除了AR的扩增、突变及其信号通路的激活外,还与雄激素代谢途径的改变相关。本文综述近年来有关CRPC肿瘤内雄激素含量的改变,及引起这些改变的原因包括雄激素新生、雄激素合成代谢酶活性变化、雄激素合成代谢酶的转运效率的改变以及肿瘤微环境相互作用的改变及其临床应用价值的最新研究进展。     

前列腺癌双极雄激素治疗的研究进展

双极雄激素治疗(bipolar androgen therapy,BAT)是去势抵抗性前列腺癌(castration resistant pros-tate cancer,CRPC)的新疗法,可显著降低部分患者血清前列腺癌特异性抗原(prostate specific antigen,PSA)水平、提高患者生活质量和恢...     

药物治疗雄激素非依赖型前列腺癌的研究进展

雄激素非依赖型前列腺癌是一高度恶性肿瘤，其药物治疗已有大量实验研究。本文总结了近年来治疗雄激素非依赖型前列腺癌的四大类药物，即酶抑制剂、抗增生药、抗转移药和促凋亡药，仅供广大医药科研工作者参考。     

雄激素受体相互作用因子在前列腺癌中的表达及其临床意义

目的 探讨雄激素受体(AR)及其相互作用因子在前列腺癌(PCa)中的表达、变异及其对肿瘤预后的影响。方法 基于STRING数据库分析AR及其相互作用因子的相互作用和GO富集;通过UALCAN分析AR及其相互作用因子在PCa中的表达;通过cBioPortal分析AR及其相互作用因子在PCa中表达变异及其与预后的关系。结果 AR及其相互作用因子相互作用网络节点为10,边数为21,平均节点度为4.2,平均局部聚类系数为0.89,其中NCOA2和EP300在AR相互作用网络中节点度最高。UALCAN分析显示RAN、TNK2、PXN和NRIP1在癌组织中上调(P<0.05);相反NCOR1在癌组织中下调(P<0.05);NCOR2、NCOA2、EP300、SOX9和RAN表达水平改变不显著。cBioPortal分析表明近30%的PCa组织中存在AR及其相互作用因子的表达变异,包括基因扩增、基因突变、深度缺失以及多重变异4个类型。AR变异率为18%,主要包括基因扩增和突变;NCOA2变异率为9%,主要变异类型为基因扩增。神经内分泌前列腺癌中的变异类型主要为基因扩增(8.7%),而去势抵...     

雄激素受体信号途径与前列腺癌

近年 ,前列腺癌 (prostate cancer,PCa)的发生率呈上升趋势 ,发生机制不清楚 ,但可以肯定是在多因素作用下 ,机体细胞死亡与存活、增殖与分化及代谢等动态平衡被破坏的结果。其中生长信号的传递对 PCa的发生发展有重要影响 ,而雄激素受体信号途径是倍受瞩目的一个。雄激素在 PCa发生发展所起的作用早为人们所认识 ,并将雄激素剥夺和抗雄激素疗法应用于临床 ,收到较好疗效。但经过激素治疗再发和 (或 )转移的病例基本上都转变为雄激素非依赖性 ,不仅对激素治疗而且对化疗药物也失去敏感性 ,这成为 PCa患者死亡的主因 ,临床医生往往束手无…     

锤头型核酶特异性阻断雄激素受体表达对前列腺癌细胞生长的影响

目的：探讨核酶阻断雄激素受体（AR）基因表达治疗前列腺癌的可能性。方法：在脂质体介导下，锤头型抗雄激素受体核酶表达载体转染前列腺癌细胞，采用逆转录－聚合酶链反应（RT－PCR）检测ARmRNA，四甲基偶氮唑盐（MTT）法检测细胞增殖活性，流式细胞仪（FCM）检测细胞周期时相，原位末端转移酶标记法检测细胞凋亡。结果：核酶表达载体转染1－5d后，前列腺癌细胞AR mRNA水平降低32．6％－40．7％（P＜0．05），细胞生长抑制率18．28％－35．34％（P＜0．05），细胞周期阻滞于G2／M期，诱导细胞凋亡，细胞凋亡比率增加20．70％（P＜0．01）。结论：应用核酶特异性切割ARmRNA，能有效阻断AR基因的表达，诱导前列腺癌细胞凋亡，有可能成为前列腺癌基因治疗的有效方法之一。     

激素抵抗型前列腺癌的治疗进展与选择

前列腺癌是一种老年男性高发疾病，在西方国家，前列腺癌是男性第二大恶性肿瘤，仅次于肺癌。据统计，2001年全球新发现前列腺癌198 100例，死亡31500例。近年来，在我国发病率也逐年上升，已列为泌尿系肿瘤的第三位，并且发病年龄也日趋年轻化。虽然前列腺癌根治性手术是治疗早期前列腺癌的根本方法，但由于临床确诊往往较晚，大部分患者失去了根治的机会，所以手术或药物去势剥夺雄激素仍是治疗晚期前列腺癌的标准方案。内分泌治疗虽然在绝大多数患者开始段可以达到肿瘤缩小、血清前列腺特异性抗原(PSA)下降，并能缓解症状，但雄激素撤除治疗2～5年内，前列腺癌从激素敏感、雄激素依赖逐渐不再对激素敏感，从而进展到激素抵抗性阶段，成为激素抵抗型前列腺癌(Hormone refractory prostate cancerHRPC).     

前列腺癌雄激素依赖转化后细胞内雄激素受体表达变化的研究

目的：探讨雄激素受体（AR）在前列腺癌雄激素依赖特性转化过程中的作用。方法：对33例晚期前列腺癌患者进行雄激素阻断治疗并作长时间随访,其间有18例发生了雄激素依赖转化．15例未发生雄激素依赖转化。采用免疫组织化学及RT—PCR法测定18例患者雄激素依赖转化前后及15例患者雄激素阻断治疗前后癌细胞内AR蛋白及AR基因的表达情况。结果：18例患者雄激素依赖转化前后AR蛋白及AR基因的表达分别为（1．33±0．97VS3．11±0．76）和（28．41±3．38Ct vs 36．73±1．81Ct）,两者之间差异有统计学意义（P〈0．01）;15例患者雄激素阻断治疗前后AR蛋白及AR基因的表达分别为（1．47±0．83 vs 1．40±0．99）和（29．50±3．08Ct vs29．14±3．23Ct）,两者之间差异无统计学意义（P〉0．05）。结论：AR基因及AR蛋白表达增强是前列腺癌雄激素依赖转化的原因之一。     

非雄激素依赖前列腺癌形成机制探讨

内分泌治疗已成为失去了手术机会的前列腺癌患者的主要治疗手段，提高了生存率。非雄激素依赖型前列腺癌出现后，内发泌治疗往往无效，患者死于肿瘤广泛转移。因此，积极探讨肿瘤异质性、雄激素受体、自分泌／旁分泌机制、癌基因与抑癌基因在非激素依赖型前列腺癌形成过程中的作用有极大价值。     

Novel non-AR therapeutic targets in castrate resistant prostate cancer

Castrate resistant prostate cancer (CRPC) remains a disease with significant morbidity and mortality. The recent approval of abiraterone and enzalutamide highlight the improvements which can be made targeting the androgen receptor (AR) axis. Nonetheless, resistance inevitably develops and there is continued interest in targeting alternate pathways which cause disease resistance and progression. Here, we review non-AR targets in CRPC, with an emphasis on novel agents now in development. This includes therapeutics which target the tumour microenvironment, the bone metastatic environment, microtubules, cellular energetics, angiogenesis, the stress response, survival proteins, intracellular signal transduction, DNA damage repair and dendritic cells. Understanding the hallmarks of prostate cancer resistance in CRPC has led to the identification and development of these new targets. We review the molecular rationale, as well at the clinical experience for each of these different classes of agents which are in clinical development.     

Treatment options for hormone-refractory prostate cancer

Surgical or medical androgen deprivation therapy in its multiple variants represents the standard therapeutic approach in the management of metastatic prostate cancer resulting in a primary response rate of about 90%. However, about 90% of the men treated will develop PSA progression within 3-4 years resulting in androgen-independent and later on hormone-refractory prostate cancer. Management of AIPCA and HRPCA still represents a therapeutic challenge despite the development of new and effective treatment options. PSA progression following primary ADT defines an androgen-refractory but still hormone-sensitive PCA which might respond to secondary hormonal manipulations such as antiandrogen withdrawal, addition of nonsteroidal antiandrogens, and administration of estrogens, ketoconazole and hydrocortisone, and somatostatin analogues. Secondary hormonal manipulations will result in a PSA decline >50% in about 60-80% of the patients with a mean duration of 7-17 months depending on the type of treatment. PSA progression following secondary endocrine treatment defines hormone-refractory prostate cancer (HRPCA) which might be treated by systemic chemotherapy. Based on the results of two prospective, randomized clinical phase III trials comparing docetaxel and mitoxantrone, docetaxel results in a statistically significant survival benefit of 2.5 months, a significantly higher PSA and pain response, and represents the treatment of choice in the management of HRPCA.Bisphosphonates such as zoledronate represent another cornerstone in the management of PSA-progressive PCA demonstrating a significant benefit with regard to the prevention of skeletal-related events. Furthermore, bisphosphonates might be indicated in the treatment of symptomatic bone pain as has been demonstrated for ibandronate and zoledronate. The current article critically reflects on the various therapeutic options in the management of PSA progression following primary androgen deprivation for advanced prostate cancer. The development, rationale, and results of systemic chemotherapy are discussed critically and a therapeutic algorithm is demonstrated.     

Therapeutic options for hormone-refractory prostate cancer

For a long time, hormone-refractory prostate cancer was regarded as a chemoresistant tumor. The introduction of taxanes has prompted a change in this opinion. For the first time treatment with 75 mg/m(2) docetaxel every 3 weeks has evidenced a survival benefit in a phase III trial (median survival of 18.9 months versus 16.5 months with mitoxantrone). Further advantages were improved pain reduction and quality of life. Neutropenia was foremost among the side effects. Docetaxel is currently the standard treatment for hormone-refractory prostate cancer.The morbidity of metastatic hormone-refractory prostate cancer is influenced by bone metastases. Pain is a prominent feature. Skeletal complications are frequent. Therapy with 4 mg zoledronic acid reduced skeletal complications significantly in comparison to placebo. The most pronounced effect is the reduction of pathological fractures. Side effects include flu-like symptoms, muscle pain, and edemas. Zoledronic acid also belongs to the standard treatment of hormone-refractory prostate cancer with bone metastases.     

Erectile dysfunction following treatment of prostate cancer: new insights and therapeutic options

Prostate cancer remains the most common cancer in adult men. Its treatment usually results in compromised or absent erectile function. This article will review the treatment options available to resume sexual activity following prostate cancer therapy and will focus on non-surgical treatment options. In addition, intracavernosal injection therapy has been shown to enhance recovery of spontaneous, unassisted erections when started shortly after nerve-sparing radical prostatectomy. Most recently, oral treatment with sildenafil citrate begun shortly after surgery was shown in a placebo-controlled trial to encourage return of normal erections. Presumably this occurs by promoting nocturnal erections which appear to prevent the permanent neurovascular damage to the penis following radical prostate surgery.     

自噬在雄激素抵抗型前列腺癌中的作用

正前列腺癌(prostate cancer,PCa)是美国等西方国家男性最常见的恶性肿瘤之一,病死率居男性各种癌症第2位~([1])。我国近年来前列腺癌的死亡率也逐渐上升,1998～2008年中国男性前列腺癌死亡率的年均增长率为8.44%~([2])。晚期PCa的治疗大多依赖于去除雄激素的方法。然而,经历18～24个月的去势治疗后,绝大多数患者均会由雄激素依赖型前列腺癌转变为非雄激素依赖型前列腺癌,即雄激素抵抗型前列腺癌(castrate resistant prostate cancer,CRPC),导致对传统的去势治疗反应效果较差~([3])。相关研究已经初步证明自噬在CRPC的进     

Use of nomograms for predicting survival in patients with castrate prostate cancer

Given the heterogeneity of prognoses in patients with castrate metastatic prostate cancer, the ability to accurately predict survival is vital for optimal patient counseling, selection of treatments, clinical trial design, and interpretation of clinical data. Over the past 20 years, several prognostic models have been developed in an attempt to refine the clinician's predictive ability. Early models were based on patients with more advanced disease. They included variables that are no longer regularly encountered today and involved cumbersome calculations that were not practical for everyday use in the clinic. Recently, 2 point-based nomograms have been developed based on pretreatment variables measured on a routine basis. These models provide a user-friendly format in which to make sophisticated predictions of survival. These models have improved our ability to predict the outcomes of patients with castrate metastatic disease. However, further work to identify novel prognostic markers to improve the accuracy of these predictions is needed.     

Therapeutic options for hormone-refractory prostate cancer in 2007

Prostate cancer is the most commonly diagnosed cancer in American men and a major health problem. While localized disease has an excellent chance for cure, metastatic disease leads to androgen-independent progression and death within a few years. Although docetaxel represents an important therapeutic milestone and is the current standard of care for metastatic hormone-refractory prostate cancer (HRPC), most patients eventually progress because of clonal selection of therapy-resistant cells or the development of cells with a drug-resistant phenotype. By understanding the molecular basis of resistance to androgen withdrawal and chemotherapy, the rational design of targeted therapeutics is possible. Over the last few years, many gene targets that regulate apoptosis, proliferation, and cell signalling have been identified, and numerous novel compounds have entered clinical trials either as single agents or in combination with cytotoxic chemotherapy. Neoadjuvant trials in particular must be further encouraged since they allow detection of biological activity in the prostatectomy specimen. This article reviews new treatment options available for men with advanced prostate cancer. Even though HRPC remains incurable, it is not untreatable. Recent findings are very promising, but challenges remain in demonstrating effective anti-tumor activity and showing a clinically relevant survival benefit in Phase III trials.