雄激素非依赖性前列腺癌发生的机制

转移性前列腺癌依然是潜在的致死性肿瘤。虽然雄激素剥夺性治疗（androgen deprivation therapy,ADT）至今仍被认为是前列腺癌最为有效的治疗手段,但大多数患者会最终发展成激素非依赖性前列腺癌而死亡。众所周知,引起雄激素受体（andro-gen-independent,AR）活化的机制在激素非依赖性前列腺癌发生过程中发挥着十分重要的作用。最新研究表明,癌干细胞（canc-er stem cells,CSC）或癌细胞的上皮-间质转化（epithelial-to-mesenchymal transition,EMT）也会促进激素非依赖性前列腺癌的进展。鉴于前列腺癌向激素非依赖性发展途径的多样性,可以想象,在改善患者生存方面取得的真正进展必将依赖于针对各种雄激素非依赖性进展途径的联合治疗。因此,本文就前列腺癌向激素非依赖性进展的相关潜在机制作一综述。     

行雄激素剥夺治疗的前列腺癌患者骨健康管理现状

雄激素剥夺治疗(androgen deprivation therapy,ADT)是前列腺癌的主要治疗方式,骨质疏松症与骨折风险的增加作为 ADT的主要不良反应,已严重威胁到前列腺癌患者的生活质量并明显增加了社会健康成本。但预防与治疗 ADT所致的骨不良事件尚未受到临床实践的足够重视。本文就ADT对于前列腺癌患者骨健康的影响,如何监测、预防与治疗 ADT所致骨质疏松症及降低骨折风险,目前全球前列腺癌患者骨健康管理的现状及其可能造成的原因,如何改进的建议等进行如下综述。     

去势抵抗前列腺癌中信号通路与miRNAs关系的研究

前列腺癌是男性泌尿生殖系统中常见的恶性肿瘤,在西方国家高居男性癌症死亡的第二位,我国前列腺癌虽然总体发病率不高,但近年来呈现显著增长的趋势。大多数转移性前列腺癌患者接受雄激素剥除治疗(ADT)可获得暂时性临床缓解,但绝大部分患者最终由雄激素依赖性前列腺癌(ADPC)转变成为去势抵抗性前列腺癌(CRPC)。这种转变的发生分子机制目前依然不是很清楚,有研究表明一些异常表达的MicroRNAs(miRNAs)参与了这种进展过程。本文综述了CRPC相关信号通路与miRNAs的研究进展,分析miRNAs在CRPC形成过程中起到的作用。     

前列腺癌患者雄激素撤除治疗后的不良事件及对策

雄激素撤除治疗（ADT）在前列腺癌治疗中占有较高比例，广泛应用于局限性进展期前列腺癌、转移性前列腺癌及前列腺癌根治术后PSA复发者。前列腺癌患者撤除雄激素的结果是使患者产生比一般中老年男子雄激素部分缺乏综合征更加强烈的雄激素缺乏症状，其中比较明显的症状包括潮热、骨质疏松／骨折、性功能障碍、贫血、乳腺发育、肌容量减少、抑郁以及全面的生活质量（QOL）降低。     

应重视雄激素撤除治疗的不良事件

雄激素撤除治疗(ADT)最初用于前列腺癌转移患者的治疗，而目前ADT适应证明显扩大，如应用于局限性进展期前列腺癌患者联合外照射放疗，可以延长生存期；改善前列腺癌根治术后PSA复发患者的生存状况。因此，接受ADT治疗5～10年以上的患者大量增加，而以往仅用于前列腺癌转移治疗的平均年限为2～5年。近年，我国前列腺癌发病有逐年增多的趋势，采用ADT治疗者仍占较高的比例，目前多数患者除重视治疗效果外，也开始重视保持良好的生活质量。因此，有必要对ADT的负面效应予以了解。     

去势抵抗性前列腺癌新型内分泌治疗耐药机制研究进展

前列腺癌是男性泌尿生殖系统最常见的恶性肿瘤之一,雄激素在其发生发展中都扮演着重要角色。经去势治疗(ADT)后绝大多数前列腺癌都会进展成为去势抵抗性前列腺癌(CRPC)。肾上腺来源的雄激素和(或)雄激素受体(AR)的改变(包括AR基因扩增)驱动了瘤内雄激素的合成,进而重新雄激素轴信号通路。目前,阿比特龙、恩扎鲁胺等抗雄激素治疗药物都是CRPC患者的一线治疗用药。但是,治疗一段时间后患者仍然会出现耐药和疾病进展。因此,明确CRPC患者抗雄激素治疗耐药机制可以为克服CRPC治疗耐药和改善CRPC患者的预后提供契机。     

雄激素去除治疗对前列腺癌患者骨代谢影响的研究

<正>自1941年Huggins和Hodges发现前列腺癌的雄激素依赖性,并采用内分泌治疗以来,雄激素去除治疗(androgen deprivation therapy,ADT)被广泛地用于前列腺癌的非手术治疗中。而当ADT治疗成功用于控制前列腺癌病程的同时,人们对它可能导致的骨质疏松却未能引起足够的重视。许多晚期前列腺癌患者在ADT过程中出现了骨代谢异常,甚至出     

雄激素受体驱动前列腺癌去势抵抗的研究进展

目前内分泌治疗仍然是前列腺癌治疗的基石, 但几乎所有前列腺癌患者治疗后均会进展为去势抵抗性前列腺癌。新型内分泌治疗药物已应用于转移性前列腺癌的一线治疗, 但仍无法避免耐药。探索雄激素受体在内分泌治疗耐药过程中的作用机制, 是破解前列腺癌耐药难题的关键。本文概述近年来雄激素受体耐药调控机制及耐药后治疗策略选择的相关研究进展。     

雌激素受体β在前列腺癌中的作用研究进展

前列腺癌是男性最常见的癌症之一,雄激素剥夺疗法(ADT)仍然是晚期前列腺癌患者的主要治疗方法,然而经过一段时间后这种方法最终会失败,患者会发展为去势抵抗性前列腺癌(CRPC),所以迫切需要新的治疗方法。越来越多的学者注意到雌激素及其受体在前列腺癌的作用,其中,雌激素受体β参与正常前列腺上皮细胞的分化及前列腺癌细胞的增殖作用,有望成为新的前列腺癌治疗靶点。本文对雌激素受体β在前列腺癌中的作用相关研究进行系统的综述。     

雄激素剥夺治疗对认知及脑功能影响的研究进展

正雄激素剥夺治疗(androgendeprivationtherapy,ADT)是前列腺癌的有效治疗手段,但亦伴随一系列不良反应。患者除躯体症状和情绪变化外,还可出现认知功能下降,痴呆风险增高,甚至脑功能改变~([1,2])。由于研究方法、随访时限及治疗药物等差异,目前对前列腺癌患者接受ADT后认知及脑功能的改变及其发生机制、临床意义尚有争议。本文将就新近相关研究进展做一综述。     

Vertebral Fractures and the Misclassification of Osteoporosis in Men With Prostate Cancer

Androgen deprivation therapy (ADT) has become the cornerstone of treatment for both advanced and nonmetastatic prostate cancer. The presence of a nontraumatic vertebral fracture (VF) identifies a patient who has clinical osteoporosis. Vertebral fracture analysis (VFA), a dual-energy X-ray absorptiometry (DXA)-based technology identifies VFs in conjunction with a standard bone mineral density (BMD) examination. The objective of this study was to determine if VFA would increase the diagnosis of osteoporosis in men with prostate cancer on ADT.One hundred sixteen men aged ≥60 yrs with nonmetastatic prostate cancer receiving ADT for ≥6 mos underwent DXA of the spine, hip, and 1/3 distal radius, VFA, and conventional vertebral X-rays.Approximately 40% of the men had clinically defined osteoporosis. The use of conventional DXA criteria (spine and hip) alone resulted in the misdiagnosis of approx 75% of patients. VFA and addition of the 1/3 distal radius site performed by DXA both increased the rate of diagnosis and reduced the misclassification of osteoporosis in men with prostate cancer, compared with conventional DXA criteria alone. Analysis indicated that VFA assessment of mild, moderate, and severe fractures from all readable vertebrae (T5–L4) had a kappa statistic, sensitivity, and specificity of 0.92, 100%, and 95%, respectively, with semiquantitative radiography.Men with prostate cancer on ADT should be screened for osteoporosis at the initiation of therapy, and evaluation should include DXA of the 1/3 distal radius in addition to the spine and hip, as well as evaluation for VFs.     

Risk factors for male osteoporosis

Hypogonadism from long-term androgen deprivation therapy (ADT), either by bilateral orchiectomy or administration of gonadotropin-releasing hormone (GnRH) agonists, causes significant and accelerated bone loss that may increase the risk of bone fractures in men with prostate cancer. Recent reports, as well as new data from our institution, have shown a high prevalence of pre-existing osteopenia and osteoporosis in men with prostate cancer before receiving ADT, and this is of great concern because of the risk of further bone loss during ADT. Data from these studies suggest the urgent need for clinical guidelines for screening, prevention, and treatment of these cases. This article reviews the prevalence and risk factors associated with osteoporosis in men and addresses risk factors in men with prostate cancer not receiving ADT. Considerations for the patient selection and timing of bone densitometry will also be discussed.     

Prostate-specific antigen and androgen deprivation therapy

Summary Prostate-specific antigen (PSA) is a kallikrein-like serine protease that, for all practical purposes, is specific for prostatic tissue. PSA is usually detected at low concentrations (0.0–4.0 ng/ml) in the serum and is the most important tumor marker for detecting otherwise unsuspected prostate cancer; it also useful for monitoring the response of prostate cancer to various types of therapy. Androgen deprivation therapy (ADT) includes bilateral orchiectomy, luteinizing hormone-releasing hormone (LHRH) agonists, antiandrogens, and 5-alpha-reductase inhibitors. Treatment of benign prostatic hypertrophy (BPH) or prostate cancer with ADT usually decreases the serum PSA concentration. Recent basic science research has demonstrated that the expression of the PSA gene is controlled by androgens acting via the androgen receptor. Therefore, in some patients a low serum PSA concentration will be the result of hormonal down-regulation of the genetic expression of PSA and not the result of the antitumorigenic activity of the therapy. Nevertheless, in spite of the direct effect of ADT on PSA expression, PSA remains a valuable prostate cancer tumor marker for prognosticating the response to ADT and portending clinical progression after this type of treatment for most patients.     

Preserving bone health in patients with hormone‐sensitive prostate cancer: the role of bisphosphonates

Men with prostate cancer initiating androgen‐deprivation therapy (ADT) may have multiple factors that threaten their skeletal health, including increased fracture risk from bone loss during ADT and the propensity to develop bone metastases, which may lead to skeletal‐related events (SREs). Bisphosphonates have utility in oncology for patients with bone metastases to prevent bone loss during hormonal therapy and in the benign setting to treat osteoporosis. These agents have an emerging role in patients with hormone‐sensitive prostate cancer (HSPC). Etidronate, alendronate, pamidronate, and zoledronic acid have all shown efficacy in preventing ADT‐related bone loss. Alendronate and zoledronic acid have also been shown to increase bone mineral density vs baseline during ADT. Patients with bone metastases from HSPC who received 4 mg zoledronic acid every 3 or 4 weeks had a low incidence of skeletal complications, although controlled study data have not been reported. Bisphosphonate treatment in men with HSPC may be effective for the prevention of ADT‐related bone loss, underscoring the importance of treating early to avoid SREs and potentially delay disease progression to metastatic bone disease.     

Hematological changes during androgen deprivation therapy

Androgen deprivation therapy (ADT) has been associated with a plethora of adverse effects, consistent with the androgen dependency of multiple reproductive and somatic tissues. One such tissue is the hemopoietic system, and one of the most predictable consequences of ADT is the development of anemia. Although anemia caused by ADT is rarely severe, ADT is often given to frail, elderly men with increased susceptibility to anemia due to multiple other causes. ADT-associated anemia may contribute to fatigue and reduced quality of life (QoL) in such men, although this requires further study. While anemia is an independent risk factor of mortality in men with prostate cancer, it is not known whether treatment of ADT-associated anemia alters clinically important outcomes, or whether treatment affects mortality. Awareness of the phenomenon of ADT-induced anemia should avoid unnecessary work-up in mild cases of normocytic normochromic anemia. However, assessment and treatment of more severe anemia may be required. This should be determined on an individual basis. In contrast to the well-described actions of ADT on erythropoiesis, its effect on other hemopoietic lineages has been less well elucidated. While preclinical studies have found roles for androgens in maturation and differentiated function of neutrophils, lymphocytes and platelets, the implications of these findings for men with prostate cancer receiving ADT require further studies.     

Immediate dual energy X-ray absorptiometry reveals a high incidence of osteoporosis in patients with advanced prostate cancer before hormonal manipulation

OBJECTIVE: To examine the incidence of osteoporosis in patients with advanced prostate cancer (using forearm densitometry) before commencing androgen deprivation therapy (ADT), as osteoporotic fractures are more frequent in patients with prostate cancer who have undergone either medical or surgical castration, because of rapid loss of bone mass. PATIENTS AND METHODS: In all, 174 patients (mean age 74.6 years, range 46-90) with advanced prostate cancer presented over 2 years. Their forearm bone densitometry values were compared with those from 106 age-matched controls (mean age 74.3 years, range 66-90). RESULTS: Of the 174 patients, 73 (42%) were osteoporotic (t score 相似文献   

Current status of primary pharmacotherapy and future perspectives toward upfront therapy for metastatic hormone‐sensitive prostate cancer

Since 1941, androgen deprivation therapy has been the primary treatment for metastatic hormone‐sensitive prostate cancer. Androgen deprivation therapy consists of several regimens that vary according to therapeutic modality, as well as treatment schedule. Androgen deprivation therapy initially shows excellent antitumor effects, such as relief of cancer‐related symptoms, tumor marker decline and tumor shrinking. However, most metastatic hormone‐sensitive prostate cancer cases eventually develop castration resistance and become lethal. Taxanes, such as docetaxel and cabazitaxel, as well as novel androgen receptor‐targeting agents, such as abiraterone acetate and enzalutamide, have emerged for metastatic castration‐resistant prostate cancer. The concept and principle of primary therapy for metastatic hormone‐sensitive prostate cancer has remained unchanged for decades. Recently, upfront docetaxel chemotherapy has been shown to prolong overall survival in men with metastatic hormone‐sensitive prostate cancer, and would lead to a paradigm shift in primary pharmacotherapy for metastatic hormone‐sensitive prostate cancer. This raises the possibility of upfront use of taxanes, as well as novel androgen receptor‐targeting agents combined with androgen deprivation therapy. The present review summarizes the current status of primary pharmacotherapy for metastatic hormone‐sensitive prostate cancer, and discusses future perspectives in this field.     

Prevention of prostate cancer by androgens: experimental paradox or clinical reality

Androgen replacement therapy in the aging male with partial androgen deficiency improved quality of life. However, such treatment is prohibited for men with a preexisting prostate cancer. The possibility of an increased risk of prostate cancer for healthy men has also been suggested on theoretical basis but recent experimental data showed that androgens may act in prevention of prostate cancer. In this review, we try to evaluate benefits and risks associated to a hormonal replacement therapy in regard to recent data. Several studies analyzing the role of testosterone for prostatic epithelial cells evidenced that testosterone acts in prostatic cell differentiation but does not have a direct role for induction of cell proliferation. Moreover, clinical studies have shown that low free testosterone levels in serum is associated with aggressive prostate cancer, like that has been observed in men with prostate cancer under prostate cancer chemoprevention by finasteride. These data suggest that an androgen pathway disruption in prostate is responsible of cell deregulations that may be associated not only with apoptosis of differentiated prostatic cells but also with potential cell transformation. The effects of androgens withdrawal for prostate cancer therapy induced in a short time the tumor arrest growth. However with time, cells adapt to low levels of androgens leading to the evolution of an androgen-independent tumor, which is more aggressive and most often fatal. The molecular mechanisms of this evolution begin to merge. A hypothesis is that such mechanisms could be initiated in elderly men with an androgen deficiency. The question is raised of whether hormonal replacement therapy could prevent prostate cancer. An encouraging recent study performed on rats demonstrated a protective effect of DHEA for prostate cancer. However, the putative role of the normalization of DHEA or other androgen levels in prevention of prostate cancer should be evaluated in clinical trials.     

Androgen deprivation therapy-associated vasomotor symptoms

Androgen deprivation therapy (ADT) is widely used as standard therapy in the treatment of locally advanced and metastatic prostate cancer. While efficacious, ADT is associated with multiple side effects, including decreased libido, erectile dysfunction, diabetes, loss of muscle tone and altered body composition, osteoporosis, lipid changes, memory loss, gynecomastia and hot flashes. The breadth of literature for the treatment of hot flashes is much smaller in men than that in women. While hormonal therapy of hot flashes has been shown to be effective, multiple non-hormonal medications and treatment methods have also been developed. This article reviews current options for the treatment of hot flashes in patients taking ADT.     

A comparison of dual energy X-ray absorptiometry of the hip and accuDEXA of the finger for the diagnosis of osteoporosis in men on androgen deprivation therapy for advanced prostate cancer

Dual energy X-ray absorptiometry (DEXA) of the hip or spine has been shown to be an effective screening tool for osteoporosis in men undergoing androgen deprivation therapy (ADT) for advanced carcinoma of the prostate. A less expensive alternative to DEXA is the use of peripheral scanners, such as accuDEXA, which measures bone mineral density (BMD) the finger. In this paper, we reviewed 59 patients on ADT who underwent both accuDEXA scan of the non-dominant hand and DEXA scan of the hip. The mean T-scores calculated by the two techniques were similar; however, the individual T-scores correlated poorly with each other. We conclude that men who require ADT for prostate cancer should undergo standard DEXA of the hip for osteoporosis screening.