EGF信号通路对雄激素非依赖性前列腺癌细胞株DU145细胞周期的影响

目的探讨EGF信号通路影响雄激素非依赖型前列腺癌细胞系DU145细胞周期分子学机理.方法MTT法检测EGF对DU145细胞增殖能力的影响,流式细胞仪检测细胞周期,Western印迹检测细胞周期调控因子的表达情况.结果EGF组细胞增殖能力显著升高,EGF组细胞在S期细胞比例为65.36%,明显高于对照组的44.32%,两者比较差异有统计学意义(P＜0.01);在蛋白质水平,EGF降低了p27表达,而CDK2、磷酸化Rb的表达不同程度增高,p16、p21表达无明显差异.结论EGF刺激导致其下游的信号通路活化,降低p27表达,并导致下游CDK2、Rb及Rb磷酸化水平的变化,最终促进了DU145细胞的增殖能力.     

激素非依赖性前列腺癌的分型治疗进展

激素非依赖性前列腺癌(HRPC)病人包括单纯高PSA水平患者、高PSA伴稳定性转移灶患者和高PSA伴进展性转移灶患者等多种类型。本文就近年来激素非依赖性前列腺癌的发病机制、临床试验的设计与评估指标、不同类型治疗方案以及新的化疗试验结果等方面的进展作一简要综述。     

信号通路药物治疗非雄激素依赖前列腺癌进展

肿瘤发展过程中生长信号起着重要作用。用分子和细胞生物学的方法来洞察信号通路已经改变了新型抗癌剂的研制。临床前的数据显示多种生长因子和它们的受体如ET、PDGF和VEGF在前列腺癌中上调,提示作用于特殊的生长信号通路的药物会对治疗有效,尤其可能成为治疗非雄激素依赖前列腺癌的突破口。我们把有关前列腺癌生长信号作用靶点临床前的论证和第一手的临床资料作一综述。     

前列腺癌激素非依赖性转化机制的研究进展

前列腺癌是老年男性泌尿生殖系的常见恶性肿瘤之一,激素非依赖性转化是前列腺癌治疗的主要障碍,是导致患者死亡的主要原因,其机制还未完全阐明.本文综述近年来雄激素受体及其信号传导、雄激素受体旁路途径、微小RNAs调控、干细胞理论、基因组学以及上皮间质转化等在前列腺癌激素非依赖性转化中的细胞和分子生物学进展.     

雄激素受体与激素非依赖性前列腺癌

目前临床主要应用内分泌治疗晚期前列腺癌.而雄激素受体(AR)在前列腺癌的进展过程中发挥作用.理解AR在前列腺癌发病及治疗中的作用就必须深入了解AR的功能特点、调节机制和异常变化机理.本文就国内外关于AR在激素非依赖性前列腺癌中的特征及引起功能障碍的作用进行综述.     

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。     

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。     

前列腺癌中Hedgehog信号通路的研究进展

晚期前列腺癌的治疗至今未取得重大进展,但最近的研究显示Hedgehog信号通路,在晚期前列腺癌(Pca)中起到重要作用。本文就Hedgehog信号通路的构成、途径及其在Pca中的研究进展作一综述。     

维生素D在治疗激素非依赖性前列腺癌中的应用

维生素D的活性代谢物骨化三醇具有抗前列腺癌细胞生长作用。其机制包括抑制肿瘤细胞增殖、介导GI期细胞阻滞、介导凋亡、减少肿瘤细胞浸润和肿瘤血管形成。骨化三醇和一些抗癌药物、细胞毒药物、地塞米松等药物合用有协同抗癌效果,毒副作用小。一些骨化三醇类似物同样具有抗癌作用,且活性更强。     

激素抵抗性前列腺癌的治疗新进展

晚期前列腺癌患者一般采用姑息性内分泌治疗,而这种治疗方式往往在2～3年后即因为雄激素抵抗失去疗效。本文就目前对激素抵抗性前列腺癌(HRPC)的几种治疗方法化疗、放疗、靶向治疗、疫苗及基因治疗等最新进展作一综述。     

Molecular-targeted therapy for hormone-refractory prostate cancer

Molecular-targeted therapy is to treat pathologic pathways specifically in tumor cell or tumor microenvironment. Specific molecular-targeted therapeutic agents for hormone-refractory prostate cancer (HRPC) include endothelin-A receptor antagonist, EGF receptor (EGFR) inhibitor, platelet derived growth factor receptor (PDGFR) inhibitor, nuclear factor of kappaB (NF-kappaB) inhibitor, cyclooxygenase-2 (COX2) inhibitor, and active form of Vitamin D. These agents have been investigated in clinical trials. So far, none of the above-mentioned agent has shown a sufficient clinical efficacy alone. However, docetaxel-based combinations with thalidomide or calcitriol have promising clinical activities. Further investigations are needed to optimize the molecular-targeted agents in the combinations with chemotherapeutic agents for the treatment of HRPC.     

丝裂原激活的蛋白激酶(MAPK)信号传导通路与膀胱肿瘤

肿瘤细胞的一个典型特征是增殖增强,其主要原因是由于细胞内信号传导通路活性增强所引起,而MAPK信号传导通路尤其重要。MAPK通路与从尿路上皮衍生而来的膀胱移行细胞癌(BTCC)的增殖作用直接有关。本文就MAPK信号通路对膀胱癌的发病原因、机理以及治疗等方面的作用的研究情况作一综述。     

Weekly paclitaxel plus estramustine combination therapy in hormone-refractory prostate cancer: A pilot study

BACKGROUND: Paclitaxel used in combination with estramustine has been shown to exert synergistic cytotoxicity in patients with hormone-refractory prostate cancer (HRPC). There have been few reports of this therapy in an Asian male population. METHODS: Nine patients with progressive metastatic HRPC completed at least one cycle of combination therapy employing weekly paclitaxel plus estramustine. Paclitaxel was given weekly for 3 weeks as a 2-h intravenous infusion at a dose of 100 mg/infusion. The cycle was repeated every 4 weeks. A dose of 280 mg of oral estramustine was administrated twice daily for 21 days from the first day of each cycle. Both efficacy and toxicity were recorded. RESULTS: Grade 1 sensory neuropathy was seen in three patients (33%) and grade 4 thrombopenia/anemia was seen in one patient (11%). Performance status improved in three of seven patients (43%), while six patients (67%) showed a 50% or greater decline in prostate-specific antigen levels. Two of these patients experienced significant improvement in bone pain. One patient died of cardiac infarction during this trial and another died of disseminated intravascular coagulopathy subsequent to gastrointestinal bleeding. An additional patient suffered non-fatal pulmonary infarction. The one-year median survival rate was 22.2% and the overall survival period was 36 weeks. CONCLUSION: Although weekly paclitaxel plus estramustine may pose a significant risk, this combination may have a beneficial effect on the quality of life HRPC patients. A well-designed phase I-II trial in an Asian male population is highly recommended.     

Chemotherapy in hormone-refractory prostate cancer

The results of the TAX 327 and SWOG 99-16 trials for the first time showed an improvement in overall survival (OS) with docetaxel-based chemotherapy in patients with metastatic hormone-refractory prostate cancer. As such, 3-weekly (q3w) docetaxel plus low-dose prednisone is widely considered to be the treatment of choice for these patients. An updated survival analysis from TAX 327 confirms that benefits observed with docetaxel are sustained at 3 years. Furthermore, q3w docetaxel plus prednisone was effective in all patient subgroups investigated, regardless of age, presence or absence of pain, and performance status. Multivariate analysis has shown that prostate-specific antigen (PSA) concentrations and kinetics (pre-treatment PSA doubling time; PSADT) are independent prognostic factors for survival in the TAX 327 cohort, along with pain, number of metastatic sites and measurable disease. Patients with baseline PSA concentrations of <114 ng/mL and PSADT > or =55 days have a median overall survival of 25 months while those with PSA concentrations of > or =114 ng/mL and a PSADT of <55 days have a median overall survival of only 14 months. A PSA decline of > or 1=30% within 3 months' therapy with docetaxel is also a surrogate of OS. Measurements such as these, and the use of predictive nomograms, can assist the physician in identifying patients at high risk of disease progression who may benefit from earlier treatment with chemotherapy.     

Therapy of hormone-refractory prostate cancer

PSA-progression following primary ADT defines an androgen-refractory but still hormone sensitive PCA which might respond to secondary hormonal manipulations. 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 2 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. The current article critically reflects the various therapeutic options in the management of PSA progression following primary androgen deprivation for advanced prostate cancer.     

The impact of altered annexin I protein levels on apoptosis and signal transduction pathways in prostate cancer cells

BACKGROUND: Although reduced expression levels of annexin I (ANX I) protein is a common finding in all stages of prostate cancer a causative relationship between ANX I dysregulation and prostate cancer development has yet to be established. METHODS: Annexin I expression was restored in LNCaP and MDA PCa 2b that normally express low or undetectable levels of ANX I protein. The impact of restoring ANX I expression on cell viability, colony formation in soft agar, apoptosis, and extracellular signal-regulated kinases (ERK), p38, c-Jun N-terminal kinases (JNK) activation was examined. RESULTS: Restoring ANX I expression reduced cell viability, colony formation, in addition to inducing apoptosis. The proliferative response of epidermal growth factor was blocked by restoring ANX I expression. Furthermore, increasing basal and induced levels of phosphorylated p38 and JNK were observed in prostate cancer cells following restoration of ANX I expression. CONCLUSIONS: Annexin I may have tumor suppressor functions in prostate cancer. The pro-apoptotic effect of ANX I involves the activation of p38 and JNK, which appears to shift the balance of signal transduction away from proliferation and toward apoptosis.     

Clinical evaluation of low dose glucocorticoid therapy for hormone-refractory prostate cancer

Fifteen cases with hormone-refractory metastatic carcinoma of the prostate were treated by the combination therapy of LH-RH analogue and low-dose glucocorticoid. Prior treatments of the patients were composed of maximum androgen blockade (MAB) therapy (14 cases) and bilateral orichiectomy (1 case). Nine of 15 cases underwent estramustine based treatment or anti-cancer chemotherapy as the second-line therapy. As a glucocorticoid (steroid) therapy, 1.5 or 2.0 mg of dexamethasone or 10 mg of predonisolone were given for a median period of nine months. Clinical responses were evaluated by the determination of serum PSA, EOD score and QOL scales. PSA responses were classified as CR, PR and PD according to the following categories; CR : PSA level decreased to less than 2 ng/ml, PR : PSA level decreased to less than half values of pretreatment level, PD: 20% or more increased to pretreatment level. PSA responses (CR + PR) were observed in eight of 15 patients for a median period of six months. Responses are seemed to be correlated with the Gleason scores. No apparent improvement on EOD scores by bone scintigraphy was seen, however, definite improvement of bone pain was identified in eight of 11 cases. The steroid therapy was considered as one of the useful treatment choice for patients with hormone-refractory prostate cancer.     

经尿道前列腺切除术治疗晚期激素非依赖性前列腺癌可行性分析

目的:探讨经尿道前列腺切除术(TURP)在晚期前列腺癌并下尿路症状(LUTS)治疗中的作用。方法:对2004～2009年诊断为晚期前列腺癌合并LUTS的43例患者进行总结,分析TURP术前及术后3、12个月患者的IPSS评分、最大尿流率、以及疾病相关危险因素。结果:术后3个月,非雄激素依赖性前列腺癌患者的IPSS[(9.58±0.33)分]、最大尿流率[(8.96±0.47)ml/s]与术前[(19.60±0.41)分、(4.93±0.68)ml/s]存在显著差异(P<0.05)。随访12个月后IPSS[(15.73±0.66)分]、最大尿流率[(15.67±0.44)ml/s]与术前相比无显著性差异。多因素分析提示术前表现为急性尿潴留的患者术后预后相对较好,激素非依赖前列腺癌患者预后差。结论:TURP治疗晚期激素非依赖前列腺癌合并LUTS的患者,在短期内可以迅速降低IPSS评分,改善生活质量;远期效果不理想。同时,手术本身也可能带来相关并发症,降低患者生存质量。