抗雄激素药物治疗去势抵抗型前列腺癌的机制研究进展

去势抵抗型前列腺癌（castration-resistant prostate cancer ,CRPC）是指经内分泌治疗产生耐药并继续发展的致命性前列腺癌,雄激素受体（androgen receptor,AR）激活途径仍是这一阶段前列腺癌发展的驱动机制,因此抗雄激素治疗仍然是重要的治疗手段之一。虽然许多新型抗雄激素治疗药物在临床治疗中显示了显著的疗效,但同时耐药也频繁出现。本文就近年来几种主要抗雄激素治疗药物的作用及相应的耐药机制进行综述。     

PlncRNA-1在雄激素非依赖去势抵抗型前列腺癌细胞中的作用

目的:探讨长链非编码RNA PlncRNA-1在雄激素非依赖的前列腺癌细胞中的作用。方法:选取雄激素依赖的前列腺癌细胞系LNCaP及雄激素非依赖的前列腺癌细胞系C4-2,应用实时定量PCR技术检测两种细胞系中PlncRNA-1的表达差异。RNA干涉技术沉默PRNCR1的表达,检测AR表达变化。流式细胞术检测细胞周期及凋亡的变化。MTT实验检测对细胞增殖的影响。细胞侵袭实验检测细胞侵袭能力的变化。结果:PlncRNA-1在雄激素非依赖的细胞系C4-2中高表达。沉默其表达可以明显降低前列腺癌细胞中AR的表达,抑制前列腺癌细胞的细胞周期、增殖及细胞的侵袭能力,并促进细胞的凋亡。结论:PlncRNA-1在前列腺癌细胞中通过调节AR,影响细胞的增殖、凋亡及细胞的侵袭能力,PlncRNA-1可能在前列腺癌CRPC进展中发挥着重要作用。     

去势治疗对前列腺癌患者骨密度的影响

为探讨去势治疗对前列腺癌患者骨密度(bone mineral density,BMD)的影响。将49例完成BMD测定的前列腺癌患者分为拟去势组21例(在开始去势治疗前即已完成BMD测定)和去势组28例(去势治疗>1年患者)2组。所有患者BMD测定均采用双能X线吸收法(dual energy X-ray absorptiometry,DEXA),BMD测定部位为腰椎(L2-4)和股骨颈。结果拟去势组62%、去势组82%均存在不同程度的BMD水平下降。在拟去势组,腰椎(L2-4)Z评分为-0.9±0.7,股骨颈Z评分为-0.6±0.5;而在去势组,腰椎(L2-4)Z评分为-1.8±1.1,股骨颈Z评分为-1.6±1.0。可见,与拟去势组相比,去势组患者BMD水平明显偏低,差异有统计学意义(腰椎BMD比较t=3.33,P=0.002;股骨颈BMD比较t=4.17,P=0.001)。初步研究结果提示,开始去势治疗前,前列腺癌患者常伴有不同程度的骨量减少和骨质疏松。去势治疗与前列腺癌患者BMD水平下降明显相关。     

甲羟孕酮治疗去势抵抗型前列腺癌的疗效观察

目的：观察甲羟孕酮对于去势抵抗型前列腺癌（CRPC）的疗效及毒副反应。方法：观察62例 CRPC患者口服甲羟孕酮后,对比口服药物前后 PSA、生活质量 KPS 评分、血红蛋白、营养状况的变化,评价药物毒副反应。结果：62例患者经过口服甲羟孕酮后,PSA 下降的有效率为11．3％、稳定率达24．2％。KPS 评分、血红蛋白较前明显改善（P 值均＜0．05）。营养状况的改善率为64．5％、稳定率达30．6％。未发现 III －IV 级毒副反应,6例出现轻度低钠血症,5例出现轻度低钾血症,Ⅰ度下肢水肿较治疗前增加4例。结论：甲羟孕酮可延缓部分 CRPC 患者的 PSA 进展,改善晚期肿瘤患者的生活质量,毒副反应小。     

去势抵抗性前列腺癌治疗新进展

 前列腺癌是男性最常见的肿瘤之一,发病率高,其中去势抵抗性前列腺癌（CRPC）治疗棘手,预后欠佳,随着对其发病机制研究的深入,近年已有新的治疗手段出现,为治疗CRPC带来新的希望。     

手术去势与药物去势治疗前列腺癌的疗效对比分析

目的：分析手术去势与药物去势治疗前列腺癌的临床治疗效果。方法选取45例前列腺癌患者作为研究对象，其中给予手术去势的22例患者为对照组，给予亮丙瑞林药物去势的23例患者为观察组，两组患者均联合比卡鲁胺行全雄激素阻断（每4周为一个周期，每天皮下注射1次），治疗6个周期后，对比治疗后两组患者的临床疗效和不良反应。结果治疗后对照组和观察组患者的治疗有效率分别为86.4%（19/22）和91.3%（21/23），但差异无统计学意义（P﹥0.05）；治疗6个周期后对照组患者和观察组患者的血清睾酮水平维持在去势水平的比例分别为91.3%（21/23）和86.4%（19/22），差异无统计学意义（P﹥0.05）；治疗后两组患者均出现潮热、胸部胀痛、疲劳、出汗等不良反应，两组差异有统计学意义（P﹤0.05）。结论亮丙瑞林药物去势与手术去势疗效相当，且不良反应少，进而避免手术去势给患者带来的风险、创伤和痛苦，具有广泛推广的价值。     

抵抗素在胰岛素抵抗及肿瘤发生中的作用

脂肪组织已经不是普通的脂肪储存仓库,近年的研究表明脂肪组织具有旺盛的内分泌功能。脂肪细胞分泌的众多脂肪因子当中,抵抗素是新近发现主要与胰岛素抵抗密切相关的脂肪因子,且与绒毛膜癌、子宫内膜癌、前列腺癌、结直肠癌、乳腺癌及胃癌的发生相关,在肿瘤发生、发展中起重要作用。     

去势抵抗型前列腺癌的研究进展

前列腺癌（prostate cancer,PCa）的发病率在我国呈明显升高的趋势。前列腺癌发生、发展与糖皮质激素的水平有着显著的关系,其中内分泌及抗雄激素治疗是PCa治疗的重点,在治疗1～2年后导致的去势抵抗型前列腺癌（castrate resistant prostate cancer,CRPC）一直是临床研究的热点。本文总结了应用新一代的抗雄激素药物阿比特龙、恩杂鲁胺等,以为临床治疗选择提供依据。     

沉默LMTK2对去势抵抗性前列腺癌PC3细胞增殖的影响

摘 要：［目的］ 研究Lemur 酪氨酸激酶2（Lemur tyrosine kinase 2,LMTK2）在去势抵抗性前列腺癌（castration resistant prostate cancer ,CRPC）中对雄激素受体（androgen receptor,AR）的调节作用并提出可能的作用机制。［方法］ 设计合成针对LMTK2基因的siRNA（siLMTK2）,阴性对照siRNA（NC）;采用瞬时转染法将以上siRNA转入前列腺癌PC3细胞,不转染的细胞设置为空白对照(Mock);采用Western blot检测转入LMTK2 siRNA对前列腺癌细胞及空白对照（Mock）中LMTK2蛋白表达的影响;通过克隆形成实验和细胞增殖实验考察沉默LMTK2基因对PC3细胞的肿瘤形成和增殖的影响。［结果］ 研究发现沉默LMTK2基因后,前列腺癌PC3细胞中LMTK2 mRNA和蛋白质表达水平显著降低;相反地,雄激素相关基因的转录显著升高。另外,LMTK2基因沉默会导致PC3细胞成瘤能力和增殖能力增强,即致癌性增强。［结论］ 本研究发现LMTK2是一种AR活性的负调节因子,沉默LMTK2基因能上调AR活性从而增强前列腺癌PC3细胞的增殖。这也为CRPC患者的治疗提供了一种新靶标,从而能够采取更有效的治疗方法。     

Maximal androgen blockade versus castration alone in patients with metastatic prostate cancer

Maximum androgen blockade （MAB）, consisting of an antiandrogen plus either a luteinizing hormone- releasing hormone agonist （LHRHA） or orchiectomy, is a standard care for patients with prostate cancer. Although, clinical trial results have been equivocal, none has shown a significant advantage in favor of MAB over castration alone in metastatic prostate cancer and MAB has been the subject of considerable controversy. The aim of this study was to compare MAB （orchiectomy or LHRHA＂Goserelin＂） and anti-androgen ＂Bicalutamide＂ with castration alone （orchiectomy or LHRHA） in previ- ously untreated metastatic prostate cancer patients. Methods： Hundred eligible patients with adequate performance status and adequate hematologic, hepatic and renal functions were included. MAB arm, fifty patients underwent castration either surgically by orchiectomy or medically by receiving Goserelin （3.6 rag） depot, which was injected subcutaneously every 28 days plus bicalutamide 50 mg once daily. Castration alone arm, fifty patients underwent castration alone either surgically by orchiectomy or medically by receiving Goserelin （3.6 mg） depot. Results： During the period from January 2011 to January 2013, with a median follow up of 18 months （range 6 to 24 months）, there were eight deaths （16%）, in MAB arm and ten deaths （20%） in castration alone arm. At three months, there were 35 patients （70%） with prostate specific antigen （PSA） normalization （-〈 4 mg/dL） in MAB arm versus 17 patients （34%） with PSA normalization in castration alone arm （P = 0.001）. The median progression free survival （PFS） times were 22.18 months （95% CI, 19.7 to 24.2 months） for MAB arm versus 22 months in castration alone arm （95% CI, 18 to 25.9 months; P = 0.045）. The survival rates for MAB arm were 82% at 18 months and 70.6% at 24 months versus 78.7% at 18 months and 75.1% at 24 months in castration alone arm （P 〉 0.05）. The median overall survival （OS） was not reached i     

Combined androgen blockade with bicalutamide for advanced prostate cancer

BACKGROUND:

A previously reported, double‐blind, randomized, multicenter phase 3 trial in 205 patients with stage C/D prostate cancer compared combined androgen blockade (CAB) with luteinizing hormone‐releasing hormone agonist (LHRH‐A) plus bicalutamide 80 mg versus LHRH‐A plus bicalutamide‐matching placebo (LHRH‐A monotherapy). The analysis at a median follow‐up of 2.4 years indicated that CAB significantly (P < .001) prolonged the time to progression and the time to treatment failure. In the current report, survival data from a long‐term follow‐up (median, 5.2 years) were analyzed.

METHODS:

All deaths irrespective of cause and all prostate cancer‐specific deaths were recorded. The data were analyzed using Cox regression analysis and the log‐rank test.

RESULTS:

At a median follow‐up of 5.2 years, a significant overall survival advantage was observed in favor of CAB over LHRH‐A monotherapy (Cox regression analysis: hazard ratio, 0.78; 95% confidence interval, 0.60‐0.99; P = .0498; log‐rank test: P = .0425). The difference in cause‐specific survival between the 2 groups was not significant. The achievement of a prostate‐specific antigen (PSA) nadir concentration ≤1 ng/mL was a prognostic factor for improved survival. More patients attained PSA nadir concentrations ≤1 ng/mL with CAB compared with patients who received LHRH‐A monotherapy (81.4% vs 33.7%; P < .001).

CONCLUSIONS:

CAB with bicalutamide 80 mg offered a significant overall survival benefit compared with LHRH‐A monotherapy without reducing tolerability in patients with locally advanced or metastatic prostate cancer. Cancer 2009. © 2009 American Cancer Society.     

Cognitive and mood changes in men undergoing intermittent combined androgen blockade for non-metastatic prostate cancer

Purpose: Men with prostate‐specific antigen (PSA)‐only relapse of prostate cancer after primary therapy are generally fully functional and asymptomatic with a life expectancy of up to 10 or more years. Androgen deprivation therapy (ADT) is a common treatment option. This study examined mood and cognitive changes in otherwise healthy men with prostate cancer prior to, during and after ADT. Experimental design: Twenty hormone naïve, eugonadal prostate cancer patients without evidence of metastases and with a rising PSA were treated with intermittent ADT consisting of 9 months of complete androgen blockade (CAB) achieved with combined leuprolide and flutamide followed by an ‘off treatment’ period. Cognitive function tests and mood measures were administered at baseline, after 3 and 9 months of ADT and after 3 months of no treatment. Twenty healthy control patients without prostate cancer range matched for age and education were tested at the same time intervals. Results: ADT patients evidenced a significant decline in spatial reasoning, spatial abilities and working memory during treatment compared with baseline. No changes were noted for measures of verbal or spatial memory, selective attention or language. Significant changes in self‐rated mood such as increased depression, tension, anxiety, fatigue and irritability were evident during treatment compared with baseline for ADT patients. No significant changes in either cognitive tests or mood measures were noted for the healthy control group. Conclusions: These findings, suggest that 9 months of combined androgen blockade may result in some adverse changes in cognition and mood. However, many but not all of these changes can return to baseline after cessation of ADT. Copyright © 2008 John Wiley & Sons, Ltd.     

晚期前列腺癌间歇与持续性内分泌治疗的临床观察

目的:观察比较晚期前列腺癌间歇性内分泌治疗(IHT)与持续性内分泌治疗(CHT)的疗效和不良反应。方法:选取确诊的晚期前列腺癌患者共96例,之前未接受治疗,随机分为:间歇治疗组(A组)和持续治疗组(B组)。A组:54例,给予比卡鲁胺(50mg,口服,每日1次)和戈舍瑞林(3.6mg,皮下注射,每月1次)治疗,当患者血清PSA≤0.2ng/ml,暂停服用药物比卡鲁胺,当患者血清PSA>4ng/ml时,重新开始服用药物比卡鲁胺。B组:42例,同时给予比卡鲁胺和戈舍瑞林治疗,不间断治疗。终止治疗的标准是病人由激素依赖转为激素抵抗性前列腺癌。比较两组治疗前、治疗后半年、1年、2年后血清PSA、疼痛缓解及排尿梗阻症状改善情况、生活质量评分、不良反应。结果:血清PSA、疼痛缓解以及排尿梗阻改善情况上,两组治疗后各时间段较治疗前均得到显著改善(P<0.05),但两组之间无显著差异(P>0.05)。A组治疗后不良反应中去势综合征、转氨酶升高、贫血以及乳房发育发生率较B组显著降低(P<0.05),生活质量评分明显升高(P<0.05)。结论:IHT和CHT对晚期前列腺癌治疗效果无明显差异,都能缓解患者的症状和提高患者的生活质量,但IHT不良反应发生率较持续治疗显著降低,生活质量明显提高,值得临床椎广。     

Effect of Intermittent Androgen Blockade on the Quality of Life of Patients with Advanced Prostate Carcinoma

OBJECTIVE To investigate the effect of intermittent androgen blockade (IAB)on the quality of life(QOL)of patients with advanced prostatic carcinoma(APC). METHODS Investigations on the QOL of 51 APC patients receiving IAB treatment,totaling 3 times,i.e.6 months before and after,and 12 months after treatment,were perform using the EORTC QLQ-C30 measuring scale and QLQ-PR25 scale. RESULTS Although IAB became an economic burden for the families,it was lessened during the intermission(P<0.05).The overall health status significantly improved 6 months after IAB treatment(P<0.01),especially during the intermission(P<0.05),with a total or local easement of pain(P<0.01)and an improvement of urinary function(P<0.01).Although there was impairment, to various degrees,in many functions of the patients on the 6th month of treatment,such as the physical function(P<0.05),role function(P<0.05),the emotional(P<0.01)and the social functions(P<0.01),with an enhancement of fatigue(P<0.01),these functions gradual y recovered by the 12th month as the intermission started.Treatment-related symptoms such as flushing and mammary swel ing significantly emerged on the 6th treatment month (P<0.01),and lessened on the 12th(P<0.01).During the treatment period, there was an notable drop in sexual interest(P<0.01),with a deprivation of sex life,but revived to various degrees during the intermission(P<0.01). CONCLUSION Although IAB treatment of APC patients did impair the physiologic and psychologic status of patients to varying degrees,these were improved and restored during the intermission.     

ACSL4 promotes prostate cancer growth,invasion and hormonal resistance

Increases in fatty acid metabolism have been demonstrated to promote the growth and survival of a variety of cancers, including prostate cancer (PCa). Here, we examine the expression and function of the fatty acid activating enzyme, long-chain fatty acyl-CoA synthetase 4 (ACSL4), in PCa. Ectopic expression of ACSL4 in ACSL4-negative PCa cells increases proliferation, migration and invasion, while ablation of ACSL4 in PCa cells expressing endogenous ACSL4 reduces cell proliferation, migration and invasion. The cell proliferative effects were observed both in vitro, as well as in vivo. Immunohistochemical analysis of human PCa tissue samples indicated ACSL4 expression is increased in malignant cells compared with adjacent benign epithelial cells, and particularly increased in castration-resistant PCa (CRPC) when compared with hormone naive PCa. In cell lines co-expressing both ACSL4 and AR, proliferation was independent of exogenous androgens, suggesting that ACSL4 expression may lead to CRPC. In support for this hypothesis, ectopic ACSL4 expression induced resistance to treatment with Casodex, via decrease in apoptosis. Our studies further indicate that ACSL4 upregulates distinct pathway proteins including p-AKT, LSD1 and β-catenin. These results suggest ACSL4 could serve as a biomarker and potential therapeutic target for CRPC.     

雄激素受体在去势抵抗性前列腺癌进展中的作用及研究进展

雄激素受体是前列腺癌发生发展的重要因素。雄激素去势疗法是目前治疗前列腺癌的标准疗法,在早期可以有效的抑制肿瘤生长。但2～3年内,肿瘤会复发或进展,形成去势抵抗性前列腺癌。目前关于雄激素去势疗法治疗后去势抵抗性前列腺癌发生发展机制研究的文献较多（其中包括类固醇激素代谢的变化、雄激素受体基因的扩增或过表达、雄激素受体辅助调节因子、雄激素受体剪接变异体、生长因子和／或细胞因子、雄激素受体突变等等机制）,但还没有对具体机制完全了解并形成共识。目前普遍认为在去势抵抗性前列腺癌中,雄激素和雄激素受体在其发生发展中起到了关键的作用。本文就雄激素受体在前列腺癌进展为去势抵抗性前列腺癌的机制中的作用加以综述。     

经尿道前列腺切除术联合间歇性或持续性雄激素阻断治疗晚期前列腺癌的疗效比较

目的探讨经尿道前列腺切除术(TUR-P)联合间歇性或持续性雄激素阻断治疗晚期前列腺癌的疗效。方法选取2007年1月至2010年5月间收治的62例晚期前列腺癌患者,按随机排列表法分为观察组和对照组,每组各31例。观察组采取TUR-P联合间歇性雄激素阻断治疗,对照组采取TUER-P联合持续性雄激素阻断治疗,比较两组患者术后3个月国际前列腺症状评分(IPSS)、生活质量评分(QOL)、残余尿量(RUV)、最大尿流率(Qmax)、3年生存率以及不良反应。结果观察组患者术后IPSS、QOL、3年总生存率分别为(7.01±1.62)分、(1.79±0.46)分和83.9%,对照组患者则分别为(7.92±1.11)分、(2.16±0.34)分和58.1%,观察组明显优于对照组,差异有统计学意义(P<0.05)。观察组患者术后RUV为(25.61±8.21)ml,Qmax为(16.13±2.98)ml/s;对照组患者术后RUV为(26.01±7.51)ml,Qmax为(15.93±3.22)ml/s。观察组患者潮热症、骨质疏松、腹泻不良反应发生率分别为19.35%、12.90%和3.23%,对照组患者分别为61.29%、35.48%和19.35%,两组差异有统计学意义(P<0.05)。结论 TUR-P联合间歇性雄激素阻断治疗晚期前列腺癌能够明显改善患者预后,减少不良反应,值得临床推广。     

Altered glucuronidation deregulates androgen dependent response profiles and signifies castration resistance in prostate cancer

Glucuronidation controls androgen levels in the prostate and the dysregulation of enzymes in this pathway is associated with castration resistant prostate cancer. UDP-glucose dehydrogenase (UGDH) produces UDP-glucuronate, the essential precursor for glucuronidation, and its expression is elevated in prostate cancer. We compared protein and metabolite levels relevant to the glucuronidation pathway in five prostate cancer patient-derived xenograft models paired with their isogenic counterparts that were selected in vivo for castration resistant (CR) recurrence. All pairs showed changes in UGDH and associated enzymes and metabolites that were consistent with those we found in an isogenic androgen dependent (AD) and CR LNCaP prostate cancer model. Ectopic overexpression of UGDH in LNCaP AD cells blunted androgen-dependent gene expression, increased proteoglycan synthesis, significantly increased cell growth compared to controls, and eliminated dose responsive growth suppression with enzalutamide treatment. In contrast, the knockdown of UGDH diminished proteoglycans, suppressed androgen dependent growth irrespective of androgens, and restored androgen sensitivity in CR cells. Importantly, the knockdown of UGDH in both LNCaP AD and CR cells dramatically sensitized these cells to enzalutamide. These results support a role for UGDH in androgen responsiveness and a target for therapeutic strategies in advanced prostate cancer.     

Concept and viability of androgen annihilation for advanced prostate cancer

There remains no standard of care for patients with a rising prostate‐specific antigen level after radical prostatectomy or radiotherapy but who have no radiographic metastases, even though this is the second largest group of patients with prostate cancer (CaP) in the United States. Androgen deprivation therapy (ADT) may cure some men with advanced CaP based on single‐institution series and a randomized clinical trial of immediate versus delayed ADT for men found to have pelvic lymph node metastasis at the time of radical prostatectomy. ADT may be more effective when initiated for minimal disease burden, which can be detected using PSA after radical prostatectomy or radiotherapy, and if more complete disruption of the androgen axis using newer agents decreases the chance that androgen‐sensitive cells survive to adapt to a low‐androgen environment. Androgens may be “annihilated” simultaneously using a luteinizing hormone‐releasing hormone antagonist or agonist to inhibit testicular production of testosterone, a P45017A1 (CYP17A1) inhibitor to diminish metabolism of testosterone via the adrenal pathway and dihydrotestosterone (DHT) via the backdoor pathway, a 5α‐reductase (SRD5A) inhibitor to diminish testosterone reduction to DHT and backdoor metabolism of progesterone substrates to DHT, and a newer antiandrogen to compete better with DHT for the androgen receptor ligand‐binding domain. Early initiation of androgen annihilation for induction as part of planned intermittent ADT should be safe, may reduce tumor burden below a threshold that allows eradication by the immune system, and may cure many men who have failed definitive local therapy. Cancer 2014;120:2628–2637 . © 2014 American Cancer Society.