类固醇受体辅活化子-1和核受体辅阻遏子在雄激素非依赖性前列腺癌的表达及临床意义

目的 探讨类固醇受体辅活化子-1（SRC-1）、核受体辅阻遏子（NCoR）在雄激素非依赖性前列腺癌（AIPC）的表达及临床意义。方法 采用免疫组化法检测20例激素依赖性前列腺癌（ADPC）、15例AIPC组织AR、SRC-1及NCoR表达。结果 1例AIPC无AR表达，其余AIPC及ADPC高表达AR。AIPC、ADPC均检测到SRC-1表达。SRC-1在AIPC的阳性率较ADPC组织明显升高（P〈0．01）。NCoR在AIPC、ADPC均有表达，但在AIPC的表达则出现明显降低（P〈0．01）。结论 SRC-1在AIPC表达升高和／或NCoR在AIPC表达降低引起的AR异常活化可能与前列腺癌（Pca）的进展有关。     

熊果酸对前列腺癌细胞雄激素非依赖性的逆转作用

目的 探讨中药成分熊果酸对雄激素非依赖性前列腺癌(AIPC)的治疗作用及其机制.方法 应用熊果酸处理体外培养的人雄激素依赖性前列腺癌(ADPC)细胞株LNCaP和AIPC细胞株DU145,噻唑蓝(MTT)比色法检测细胞活性及对人工合成雄激素R1881的反应性,免疫细胞化学检测熊果酸对雄激素受体(AR)、糖皮质激素受体(GR)、前列腺特异性抗原(PSA)及成活因子HSP90和白细胞介素(IL)-6表达的影响,逆转录.聚合酶链反应(RT-PCR)检测熊果酸对DU145细胞AR mRNA表达的影响.结果 熊果酸对不同浓度雄激素下的LNCaP细胞均呈浓度和时间依赖性生长抑制,20 mg/L的熊果酸作用96 h对LNCaP细胞的抑制率近50%.0.1 nmoL/L的R1881为最适生长浓度,熊果酸作用后,LNCaP细胞生长的最适雄激素浓度上升了10倍;熊果酸对DU145细胞的生长有浓度和时间依赖性抑制效应,DU145细胞对AR阻断剂羟氟他胺缺乏反应,熊果酸作用同时再应用氟他胺比单纯熊果酸的作用更明显,对细胞抑制率明显上升.熊果酸作用后,LNCaP和DUl45细胞IL-6、HSF90表达均明显下降(P＜0.05),DU145细胞GR表达明显降低(P＜0.01),AR和PSA蛋白及AR mRNA出现再表达.结论 熊果酸能改善前列腺癌细胞对雄激素的反应性,使LNCaP细胞对雄激素的依赖性加强,并诱发了DU145细胞对雄激素的反应性,其部分机制是降低了GR、HSP90、IL-6的表达并促进AR再表达.     

雄激素非依赖性前列腺癌和雄激素受体的研究进展

晚期前列腺癌可发生雄激素依赖性改变,对抗雄激素治疗不再有效.前列腺癌对雄激素依赖性发生转变的分子机制目前尚未完全阐明,近年来的大量研究显示前列腺癌雄激素非依赖性与雄激素受体(androgen receptor,AR)的反常激活有关,与雄激素受体(AR)表达增加和突变、AR调节因子表达改变、AR信号途径改变有关,但AR在雄激素非依赖性前列腺癌中的作用仍不清楚,本文就这些方面的研究进展作一综述.     

雄激素非依赖型前列腺癌中雄激素受体特征改变的研究进展

前列腺癌在欧美国家高龄男性中发病率较高,在我国的发病率近年来也有明显的上升趋势.雄激素在前列腺癌细胞的生长、转移中起决定性作用,雄激素只有和雄激素受体( androgen receptor,AR)相结合才能发挥作用.在前列腺癌发病前期,肿瘤细胞多为雄激素依赖型,去势治疗有一定疗效.但随着治疗时间延长,部分患者可转变为雄激素非依赖前列腺癌( androgen-independent prostate cancer,AIPC).研究AIPC中AR的相关改变可以帮助我们进一步探索AIPC的成因,为临床治疗提供思路.现就AIPC中与AR相关改变综述如下.     

前列腺癌雄激素非依赖性相关研究的进展

前列腺癌的雄激素依赖性使得前列腺的内分泌治疗成为可能。但是 ,最终前列腺癌都转化为雄激素非依赖性前列腺癌 (androgen independentprostatecancer,AIPC) ,并因此死亡。如果能够明确前列腺癌的雄激素非依赖性发生机理 ,就能够提出针对性的治疗方法。本文详细综述了AIPC的可能发生机理 ,并对未来AIPC的治疗提出了方向。     

雄激素受体与激素非依赖性前列腺癌

晚期前列腺癌可发生激素非依赖,对抗雄激素治疗不再有效。前列腺癌对雄激素依赖性发生变化的机制目前尚未阐明,近年来的研究显示前列腺癌雄激素非依赖性与雄激素受体(AR)的反常激活有关,与雄激素受体(AR)表达增加和突变、AR调节因子表达改变有关,细胞因子IL-6、IL-4,糖原合成激酶-3β参与激素非依赖性前列腺癌的AR激活。本文就这方面的研究进展作一综述。     

雄激素受体与激素非依赖性前列腺癌

晚期前列腺癌可发生激素非依赖，对抗雄激素治疗不再有效。前列腺癌对雄激素依赖性发生变化的机制目前尚未阐明，近年来的研究显示前列腺癌雄激素非依赖性与雄激素受体(AR)的反常激活有关，与雄激素受体(AR)表达增加和突变、AR调节因子表达改变有关，细胞因子IL-6、IL-4，糖原合成激酶-3β参与激素非依赖性前列腺癌的AR激活。本文就这方面的研究进展作一综述。     

miR-221通过作用DVL2影响前列腺癌细胞系的侵袭功能

目的 评价miR-221在前列腺癌细胞系中表达的变化对其神经内分泌样转化及其侵袭功能的影响.方法 以Northern blot检测LNCaP、LNCaP-AI两种前列腺癌细胞系中7种microRNA的表达变化;细胞转染法检测在雄激素剥夺环境中LNCaP和LNCaP-AI细胞系中miR-221的作用;CCK-8法检测细胞在不同阶段的生长增殖水平;Transwell法检测转染细胞的侵袭能力;qRT-PCR和Western blot检测转染的细胞中神经元特异性烯醇化酶(NSE)及dishevelled-2( DVL2)表达的变化.结果 与雄激素依赖性前列腺癌(ADPC)的细胞系LNCaP相比,miR-221在雄激素非依赖性前列腺癌(AIPC)的细胞系LNCaP-AI中明显高表达.通过转染使miR-221在LNCaP细胞系中高表达可促进细胞的NSE表达,加速其神经内分泌样分化.而在LNCaP-AI细胞系中下调miR-221水平则会升高靶基因DVL2的表达水平,并增强LNCaP-AI细胞的迁移和侵袭能力.结论 该实验证实在AIPC和ADPC细胞系中miR-221存在表达差异.miR-221可促进前列腺癌细胞的神经内分泌样转化,这可能是导致前列腺癌雄激素非依赖转化的重要原因.MiR-221可通过作用DVI2调节晚期前列腺癌细胞的转移和侵袭.     

抗雄激素药物撤退治疗雄激素非依赖性晚期转移性前列腺癌的疗效分析与预测

目的 寻找预测抗雄激素药物撤退治疗雄激素非依赖性晚期转移性前列腺癌有效性的相关因素.方法 晚期转移性前列腺癌患者347例,均接受最大程度雄激素阻断治疗.其中失效进展为雄激素非依赖性前列腺癌(AIPC)237例,接受抗雄激素药物撤退治疗90例.对90例患者进行随访,末次随访时间2009年9月30日.将内分泌治疗前基线血清PSA、Gleason评分(GS)、临床分期、去势方案、抗雄激素药物方案、内分泌治疗过程中血清PSA最低值、达到PSA最低值时间、进展为AIPC时PSA速率(PSAV)、进展为AIPC时PSA倍增时间(PSADT)、内分泌治疗有效时间、进展为AIPC时年龄、抗雄激素药物撤退治疗前PSA作为预测抗雄激素药物撤退治疗是否有效的预测因素,行Logistic单因素及多因素回归分析.结果 90例患者中具有完整随访资料87例,其中有效17例(19.5%),无效70例(80.5%).至末次随访时,失效14例,仍有效3例.抗雄激素药物撤退治疗中位有效时间4个月.单因素分析结果显示,进展为AIPC时PSAV(P=0.033)、进展为AIPC时PSADT(P=0.009)和抗雄激素药物撤退治疗前PSA(P=0.002)为抗雄激素药物撤退治疗有效性的预测因素.多因素分析结果显示:进展为AIPC时PSAV(P=0.042)和PSADT(P=0.036)为抗雄激素药物撤退治疗有效性的独立预测因素.结论 进展为AIPC时PSAV和PSADT为预测抗雄激素药物撤退治疗有效性的独立预测因素.     

HER-2/neu与雄激素非依赖性前列腺癌

前列腺癌开始时属于雄激素依赖性，在接受药物或手术睾丸去势治疗后肿瘤退缩，但最终还是会转变为雄激素非依赖性而继续生长。研究发现多数雄激素非依赖性前列腺癌持续表达雄激素受体(AR)和雄激素依赖性基因前列腺特异性抗原(PSA)，这说明尽管已处于睾酮去势水平，这些细胞中仍保持着AR信号通路。现有的解释是，AR激素结合区的扩增或突变改变了AR的结合功能，     

Partial androgen insensitivity syndrome with thermolability in the androgen receptor

We report case of partial androgen insensitivity syndrome in a 12-year-old boy referred to our clinic complaining of bilateral gynecomastia and left undescended testicle. Laparoscopy for undescended testicle and bilateral mastectomy were performed, and the left testicle was absent. When skin fibroblasts of the scrotum obtained during surgery were cultured to analyse the androgen receptors, a slight thermolability was observed. Genomic examination of the androgen receptor gene could not detect any mutations.     

Gleason score predicts androgen independent progression after androgen deprivation therapy

OBJECTIVE: The Gleason system is the most widely utilized histologic grading system for prostate cancer and a powerful predictor of cancer behavior. In this study, we evaluated the prognostic value of the Gleason grading system in predicting progression to androgen independent prostate cancer (AIPC). METHODS: Records from 150 patients with advanced or metastatic prostate cancer treated with androgen deprivation therapy (ADT) were retrospectively reviewed. Androgen independent progression was defined as two consecutive elevations of serum prostate specific antigen (PSA) above the nadir value. Kaplan-Meier and the Cox proportional hazards methods were used to assess potential predictors of progression to AIPC. RESULTS: Patients with low and moderate Gleason scores experienced significantly longer remissions compared to those with Gleason score of 8-10 (p=0.0006, Log-Rank test). The cumulative hazard of progressing to AIPC increased by almost 70% for each unit increase in total Gleason score. CONCLUSION: In this patient cohort the Gleason score was the only independent predictor of progression to AIPC.     

Novel androgen receptor gene mutation in patient with complete androgen insensitivity syndrome

To present a rare case of a patient probably with complete androgen insensitivity syndrome (CAIS) and studied its potential genetic cause. A 24-year-old woman with a normal-appearing vulva and vagina presented to us because of primary amenorrhea. Imaging studies showed no uterus or ovary development but inguinal cryptorchism. Histopathologic examination revealed normal testicular structures. Sequencing the CAIS-associated androgen receptor gene revealed a novel missense mutation of T to G (F698L). A novel androgen receptor gene mutation in the ligand binding domain was detected in the present patient with CAIS, supporting the important role of an androgen receptor defect in the etiology of CAIS.     

Risks of androgen therapy

Elderly men with clinical and laboratory evidence of androgen deficiency are eligible for testosterone treatment.

With proper monitoring this is acceptably safe.

In the first year of testosterone treatment there should be a digital rectal examination of the prostate and measurement of prostate specific antigen every three months, thereafter yearly.

The rate of increase of prostate specific antigen (PSA) levels is more significant than its absolute values.

Levels of haemoglobin and the haematocrit should be monitored.     

雄激素的代谢作用

睾丸分泌的雄激素中最重要的是睾酮 ,睾酮对胚胎时期生殖导管和尿生殖窦的分化、精子发生、第二性征的发育和维持、青春期身体的直线生长、性功能以及对下丘脑 -垂体的反馈调节等均起着关键性作用。近年来对睾酮在非性器官的生理性和病理性作用产生了兴趣 ,随着科学技术的进步、经济状况的改善和人均寿命的提高 ,心血管疾病和糖尿病等代谢性疾病已成为人类的主要杀手 ,因此 ,对雄激素代谢作用的关注也在情理之中 ,现将近几年关于雄激素代谢作用的研究成果介绍如下。雄激素的蛋白代谢作用自 Kenyon等 ( 1 940 )用丙酸睾酮治疗睾丸功能减退成…     

Duration of androgen deprivation therapy with maximum androgen blockade for localized prostate cancer

Background

In this study, by comparing TVT surgery and TOT surgery for stress urinary incontinence in women, the characteristics and learning curves of both operative methods were studied.

Methods

A total of 83 women with stress urinary incontinence treated with tension-free vaginal tape (TVT) (n = 38) or transobturator tape (TOT) (n = 45) at Saiseikai Central Hospital between April 2004 and September 2009 were included. We compare the outcomes and learning curves between TVT surgery and TOT surgery. In statistical analysis, Student's t test, Fisher's exact test, and Mann-Whitney's U test were used.

Results

The surgical durations were 37.4 ± 15.7 minutes with TVT surgery and 31.0 ± 8.3 minutes with TOT surgery. A longer period of time was required for TVT surgery (p = 0.025). The residual urine at post-operative day 1 was higher in TVT surgery (25.9 ± 44.2 ml) than in TOT surgery (10.6 ± 19.2 ml) (p = 0.0452). The surgical duration of TVT surgery was shortened after the operator had performed 15 operations (p = 0.019).

Conclusions

In comparison of TVT surgery and TOT surgery, the surgical duration of TVT surgery was longer and the residual urine of TVT surgery was higher at post-operative day 1. Surgical experience could shorten the duration of TVT surgery.