【作者】 古炽明；

【导师】 陈志强；

【作者基本信息】 广州中医药大学 ， 中医外科学， 2009， 博士

【摘要】 前列腺癌是泌尿外科最常见的肿瘤之一,我国近年来发病率不断上升,已跃居泌尿生殖系恶性肿瘤的第3位。内分泌治疗是前列腺癌目前最主要的治疗方法,但现有研究表明,经过中位时间14～30个月后,大部患者经治疗后最终都转为激素非依赖性前列腺癌。因此,寻求有效治疗激素非依赖性前列腺癌的途径,以提高激素非依赖性前列腺癌患者的生存质量、延长其生存期,成为目前及今后一个阶段医学迫切需要解决的问题。中医药是防治肿瘤的有效方法之一,众多研究抗肿瘤疗效及机制的结果都表明,调节患者免疫功能,使患者重建免疫功能平衡或提高患者免疫功能,从而有效发挥免疫的抗肿瘤机制,是其最重要的机理之一。在前期对晚期前列腺癌病因病机、辨证分型及运用中西医结合扶正以抑瘤的方法治疗晚期前列腺癌临床证实有效的研究基础上,通过专家意见征询总结,再次拟定中西医结合前列腺癌的诊疗工作手册,规范本院前列腺癌诊疗工作;对激素非依赖性前列腺癌的病因病机进行进一步总结,认识到激素非依赖性前列腺癌的病机以虚虚为本,故导师陈志强教授提出扶正以抑瘤理论,治疗上以补虚为主、祛邪为辅,在临床中取得一定疗效。并通过实验研究方面以扶正抑瘤法组方的含药血清对PC-3细胞进行体外实验,结果显示以扶正抑瘤法组方的含药血清能抑制人前列腺癌PC-3细胞的增殖,且呈剂量、浓度依赖性,其抗肿瘤活性可能与诱导肿瘤细胞凋亡有关;从细胞学角度再次证实扶正抑瘤法对激素非依赖性前列腺癌细胞具有抑制其增殖及诱导癌细胞凋亡的作用。在此基础上,本研究拟探讨激素非依赖性前列腺癌与细胞免疫水平的相关性,并观察扶正抑瘤法治疗激素非依赖性前列腺癌的临床疗效及可能的作用机理,从而为中西医结合有效治疗激素非依赖性前列腺癌提供临床依据。目的探讨激素非依赖性前列腺癌细胞免疫水平变化,评价扶正抑瘤法治疗激素非依赖性前列腺癌的疗效及对其细胞免疫水平影响。方法以36例激素依赖性前列腺癌患者作为研究对象,39例激素依赖期前列腺癌患者作为研究对照组。使用流式细胞仪技术（FCM）测定其外周血T淋巴细胞亚群（CD₃⁺、CD₄⁺、CD₈⁺）及NK细胞(CD_（16+56）⁺)水平变化。同时按治疗方法差异自然入选分组的队列研究方法,将36例激素依赖性前列腺癌患者又分为治疗组及对照组,对照组予以现行“前列腺癌诊断治疗指南”二线内分泌治疗,治疗组在二线内分泌治疗基础上予以患者扶正抑瘤法中医药治疗,均在治疗前后记录患者临床症状变化、测定其血清前列腺特异性抗原（PSA）变化、B超检查局部病灶的变化、行Karnofsky行为量表评分;治疗组及对照组均在治疗3个月后再次取外周血以FCM测定其CD₃⁺、CD₄⁺、CD₄⁺及CD₉₁₆₊₅₆)⁺水平。结果治疗前激素非依赖性前列腺癌患者CD₃⁺T、CD_<sup>+T及CD₈⁺T水平均明显下降,与前列腺癌激素依赖期患者（对照组）比较差异有统计学意义（P＜0.05）。CD_（16+56）⁺N水平亦下降明显,与对照组比较差异有统计学意义。但CD₄⁺/CD₈⁺比值上升,与对照组比较差异无统计学意义。经治疗后,在临床症状改善方面:治疗组临床有效率为78.94%,对照组有效率为62.5%。而在PSA水平控制方面:治疗组PSA值下降＞50%者14例,有效率为73.68%;PSA持续上升者2例,对照组PSA值下降＞50%者7例,有效率为43.75%;Ridit分析均示差异有统计学意义（P＜0.05）。在生存质量评分方面:治疗组的Karnofsky评分在治疗后与治疗前比较差异有统计学意义（P＜0.01）。虽然对照组虽经治疗后Karnofsky评分稍升高,但前后对比差异无统计学意义。在细胞免疫水平方面:治疗组在CD₃⁺及CD₄⁺水平在治疗前后比较差异有统计学意义（P＜0.05）,对照组的CD₃⁺、CD₄⁺水平在治疗前后对比均无统计学意义。虽然治疗组CD8+水平治疗后较治疗前轻微下调,而对照组CD₈⁺水平治疗后较治疗前轻微上调,治疗前后对比差异均无统计学意义。CD₄⁺/CD₈⁺T比值治疗组经治疗后明显提高,前后对比差异有统计学意义（P＜0.05）;而对照组的CD₄⁺/CD₈⁺T比值在治疗前后对比差异无统计学意义。治疗组的CD_（16+56）⁺N水平经治疗后上调,在治疗前后比较差异有统计学意义（P＜0.05）。而对照组的CD_（16+56）⁺N水平在治疗前后对比无统计学意义,经治疗后CD_（16+56）⁺N水平反而下降。结论激素非依赖性前列腺癌患者整体CD₃⁺、CD₄⁺、CD₈⁺及CD_（16+56）⁺水平下降;扶正抑瘤法能有效改善激素非依赖性前列腺癌患者临床症状,控制PSA水平,明显改善患者生存质量;经扶正抑瘤法治疗后,治疗组患者CD₃⁺、CD₄⁺及CD_（16+56）⁺水平明显上调。提示激素非依赖性前列腺癌癌患者细胞免疫水平明显下降或受抑制、紊乱,扶正抑瘤法能有效治疗激素非依赖性前列腺癌,作用机制可能与调节患者细胞免疫水平有关。更多还原

【Abstract】 Prostate cancer is one of the most common urology tumor,in recent years, the incidence of prostate cancer is rising continuously in China,and now it has become the third common tumors of Urogenital.Endocrine therapy for prostate cancer is currently the main treatment,but now studies have shown that after amedian survival time of 14 to 30 months,most patients eventually are transformed to hormone independent prostate cancer.Therefore,it is an urgent problem need to be resolved that how to find effective treatment for hormone independent prostate cancer to enhancing quality of life of the patients and prolonging their survival time.Traitional Chinese Medicine（TCM） is an effective way to prevent and cure cancer,one of the important anti-tumor mechanisms is found that to regulate the immune function of patients,so that to reconstruct the immune balance function of patients or enhance the immune function.According to TCM theory,hormone independent prostate cancer is an extreme deficient disease,so my tutor professor Chen Zhiqiang proposes the theory of Fuzheng aiming to Yiliu,point to treating patients by tonifying deficient symptoms,and it had gained fine effects in clinical.This study is to investigate the relevance between hormone independent prostate cancer and cell-mediated immunity,and to observe the clinical efficacy and possible mechanism of Fuzhengyiliu therapy for hormone independent prostatecancer,therefore to provide clinical basis for the effective treatment of hormone-dependent of prostate combining TCM with western medicine.ObjectiveTo investigate the changes of cell-mediated immunity of hormone independent prostate cancer,evaluate the clinical efficacy of patients treated by Fuzhengyiliu therapy and its impact on the level of cell-mediated immunity. Methods36 cases of patients with hormone independent prostate cancer were selected to be studyed,and 39 cases with prostate cancer in hormone dependent period were selected as control study group,T lymphocyte subsets（CD₃⁺、CD₄⁺、CD₈⁺） and Nature Killer cell(CD_（16+56）^-+) activities in peripheral blood of all patients were detected by Flow cytometry（FCM）.At the same time,36 cases of patients with hormone independent prostate cancer were divided into two groups（treatment group and control group）according to different treatment methods in the light of cohort study method.The control group was treated by the current second-line endocrine therapy,and the treatment group was treated by the second-line hormonal therapy and Fuzheng yiliu therapy.Before and after treatment,the changes of clinical symptoms,peripheral serum prostate specific antigen（pSA） and the changes of local lesions of all patients were detected,and also all were gived a mark of the Karnofsky Scale score:After treating for three months,the treatment group and control group were decected the level of peripheral blood CD₃⁺、CD₄⁺、CD₈⁺ and CD_（16+56）⁺ again.ResultsAs compared with the control study group（the patients with hormone dependent period prostate cancer）,the level of CD₃⁺T、CD₄⁺T and CD₈⁺T were significantly decreased before treating in hormone independent prostate cancer patients,and the difference was statistically significant（P＜0.05）. And the level of CD_（16+56）⁺N of hormone independent prostate cancer also decreased significantly when compared with the control study group.However,the ratio of CD₈⁺/CD₈⁺ increased,the difference was not statistically significant compared with the control study group.After the treatment,The effective rate of the Fuzhengyiliu therapy group was 78.94%,and the control group was 56.25%in clinical symptoms,In controlling of PSA levels,there were 14 cases who had been found decreased more than 50%in Fuzhengyiliu therapy group,and 2 cases continued to rise; And there were 7 cases decreased by more than 50%in control group;That is to say,the effective rate of Fuzhengyiliu therapy group was 73.68%and the control group was 43.75%in pSA levels,and there was significant difference in statistics between Fuzhengyiliu therapy group and control group according to Ridit analysis method（P<0.05）.Furthermore,on quality of life scored by the Karnofsky Scale score method,it also has significant statistical difference between the pro-treatment and the pre-treatment of the Fuzhengyiliu therapy group（P<0.01）.After the treatment,the Karnofsky score of the control group slightly increased,however,there was no statistic difference when comparing patients after treatment with pre-treatment patients.In the cell-mediated immunity,the CD₃⁺ and CD₈⁺ level in Fuzhengyiliu therapy group showed significant statistic differences when after treatment patients compared with before treatment（P<0.05）,but no significant difference was found in the control group of those index.The CD₈⁺ level in the Fuzhengyiliu therapy group decreased slightly after the treatment,while increased slightly in the control group after the treatment,however,there was no statistic difference in both of them.The ratio of CD₄⁺/CD₈⁺ T in the Fuzhengyiliu therapy group increased distinctly after the treatment（P<0.05）,but those in the control group had no obvious difference. The level of CD_（16+56）⁺ in the Fuzhengyiliu therapy group had increased significantly after treatment（P<0.05）,while that in the control group decreased,and there was no obvious difference comparing patients before treatment with those after treatment.ConclusionThe level of CD₃⁺、CD₄⁺、CD₈⁺ and CD_（16+56）⁺ were decreased overall in hormone independent prostate cancer patients;Fuzhengyiliu therapy could improve the clinical symptoms effectively,control the level of pSA,and evidently improve the quality of life of the patients;After treated by Fuzhengyiliu therapy,the level of CD₃⁺,CD₄⁺ and CD_（16+56）⁺ were significantly raised.It is suggested that there is a dysfunction condition mainly suppressed or significantly decreased in cell-mediated immunity function of patients with hormone independent prostate cancer;Fuzheng Yiliu therapy could treat the patients effectively, probably by adjusting the level of cell-mediated immunity of the patients.更多还原