中药消水Ⅱ号外敷治疗恶性胸水的临床与实验研究
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摘要
目的：恶性胸腔积液(malignancy pleural effusion MPE)是恶性肿瘤的常见并发症，绝大多数的恶性肿瘤都可以引起胸水，肺癌并发胸水者比例相当高，约占24%～42%，尤其是肺腺癌胸水发生率约为37%以上。胸水的出现常常意味着病变已局部或全身播散，预后很差，生存期短。临床上恶性肿瘤病人一旦出现胸腔积液，就严重地影响患者的生活质量，如不及时治疗，即可危及生命。因此，积极治疗胸腔积液是延长中晚期肿瘤患者生存期和提高生存质量的有效措施之一。
消水II号外敷是导师李佩文教授根据祖国医学“内病外治”的理论和多年来治疗癌性积液的经验组成的中药外治复方，通过动物实验证明腹水中有较高活性成分含量，可延长H22腹水小鼠生存期，诱导细胞凋亡，对腹水临床疗效较好，而且应用方便，毒副作用小，药源广，经济实惠，患者乐于接受。我们在以前消水II号外敷治疗腹水的临床及实验研究的基础上，继续探讨消水II号外敷对胸水的临床疗效及其机制，观察消水II号外敷对非小细胞肺癌恶性胸水的疗效及其对晚期癌症患者治疗中生活质量、生存期和胸水生化指标的动态化关系，进一步阐述中医药治疗晚期肺癌并发症胸水的疗效特点和作用机理。
方法：临床部分：（1）将40例肺癌胸水患者随机分为消水II号外敷组和顺铂胸腔灌注组，每组各20例。消水II号外敷组将药物外敷在患侧胸壁，每天更换一次。连续治疗4个星期。顺铂胸腔灌注组用顺铂，每周一次，每次40mg，用40ml生理盐水溶解，尽量抽取胸水，然后注射胸腔，连用4次。按照疗效评价标准，观察两组患者胸水治疗缓解率。（2）采用国际通用的肺癌生活质量问卷（EORTC QLQ-C30-L13）调查，对生活质量状况进行评价。（3）观察两组之间的生存期。（4）治疗前和治疗后常规采取胸水，采用ELISA双抗夹心法检测胸水中CD44v6、MMP-2、MMP-9、IL-2、IFN-γ、sIL-2R及胸水中NK活性、CD4+/CD8+比值。（4）采用前进法多因素分析治疗后MMP-9、MMP-2、CD44v6、缓解率、QOL、CD4+/CD8+的变化对生存率的影响。并分析独立因素对生存的影响。
实验部分：（1）建立人肺腺癌A549细胞裸小鼠胸膜转移模型，共分3组，基质对照组、顺铂治疗组、消水II号外敷组。每组各10只，观察3组小鼠体重、摄食量、生存期以及肿瘤细胞在胸膜腔的浸润程度。（2）采集肿瘤组织标本，用免疫组化法观察瘤体组织中CD44v6、MMP-2、MMP-9、TIMP-1、TIMP-2的表达情况。
结果：临床方面：（1）两组治疗后DDP组完全缓解（CR）9例；部分缓解（PR）6例；无效（NC）5例，缓解率（CR+PR）为75%，消水II号组完全缓解（CR）7例；部分缓解（PR）7例；无效（NC）6例，缓解率（CR+PR）为70%。两组无明显差异。显示消水II号可达到和DDP胸腔内注射同等样效果。（2）对生活质量状况的评价结果：消水II号组和顺铂治疗组都可以增加评分，消水II号组平均提高17分，而DDP组平均提高5分，经t检验两组有显著差异（p<0.05）。（3）延长生存期，DDP治疗组平均生存时间139天，中位生存时间为134天，消水II号组平均生存时间171天，中位生存时间为170天，两组之间有明显的差异（p<0.05）。（4）影响生存率的多因素分析结果：MMP-9、MMP-2、CD44v6、缓解率、QOL对生存时间都有影响，对生存影响的风险比率顺序为治疗方式、MMP-2、MMP-9、生活质量、CD44v6。（5）胸水中免疫指标和粘附分子的变化：治疗后消水II号外敷组胸水中CD44v6、IL-2、IFN-γ水平有所升高、NK、T细胞亚群活性增高。胸水中MMP-2、MMP-9、sIL-2R的水平下降。顺铂治疗组CD44v6、IL-2、IFN-γ、sIL-2R、MMP-9水平降低、NK、T细胞亚群活性降低。
实验方面：（1）消水II号外敷后肿瘤细胞在胸腔里的浸润程度明显减轻，与基质对照组比有差异显著。（2）延长小鼠生存期：DDP组中位生存时间为36天，消水II号组为43天。消水II号组中位生存时间明显长于顺铂治疗组（p<0.01）。说明消水II号外敷治疗能延长模型小鼠的生存时间。（3）免疫组化法观察结果显示：消水II号外敷后瘤体组织中CD44v6、MMP-9、MMP-2表达减弱，与基质对照组比有显著差异（p<0.05）。TIMP-1、TIMP-2的表达增强，与基质对照组比有显著差异（p<0.05）。
结论：（1）消水II号外敷治疗恶性胸水的缓解率和顺铂相当。（2）消水II号外敷治疗恶性胸水可以提高患者的生活质量。缓解临床症状，而且对机体无毒副作用，应用方便、患者乐于接受。（3）通过稳定病灶，有效延长肿瘤患者的生存期。多因素分析影响生存率的因素显示：治疗方式、缓解情况、MMP-2对生存影响最大。提示消水II号治疗后缓解的重要性，对缓解情况、生活质量、MMP-2、MMP-9的单因素分析显示，都为独立预后因素。（4）提高胸水中CD44v6、IL-2、IFN-γ水平、增加NK活性。降低胸水中MMP-2、MMP-9、sIL-2R的水平。提示消水II号外敷能活化免疫细胞，促进胸膜粘连，减少胸水的渗出。（5）抑制肿瘤细胞粘附分子CD44v6的表达、保持TIMPs和MMPs之间的平衡，降低肿瘤细胞的恶性程度，从而抑制了肿瘤的转移。
Purpose: malignant pleural effusion (MPE) was the common complication of carcinoma. Pulmonary carcinoma was the most common carcinoma complicated by pleural effusion， especially adenocarcinoma，which complication rate was 37%. Pleural effusion indicated the disease had diffused locally or widely. So，treating the pleural effusion actively was the effective method to prolong the survival time and improve the quality of life.
XiaoshuiⅡ was exterior compound according to the principle of " treating the inner diseases by exterior medicine" of TCM. And there had been some animal experiments and clinical trials studying to its effect. Basing on those studies，the effect and mechanism of XiaoshuiⅡ were researched in this study.
Methods: clinical trial: forty lung cancer patients with pleural effusion were divided into two groups，XiaoshuiⅡ group and Cisplatin (DDP) group. The patients of XiaoshuiⅡ group were given XiaoshuiⅡ external used on the thoracic wall for 4 weeks， changed every 2 days. Cisplatin，40mg solved in 40ml saline，was injected into the thoracic cavities of the patients in Cisplatin group every week for 4 weeks. The quality of life (QoL) and survival time were evaluated. In addition，ELISA was used to examine the CD44v6， MMP-2，MMP-9，IL-2，IFN-γ，sIL-2R，activity of NK and T subset in pleural effusion respectively before and after treatment. The effect of survival rate related with the change of MMP-9，MMP-2，CD44v6， remission rate， QoL and CD4/CD8 was analysed by COX analysis.
Animal experiment: at first，the pleura metastasis model of human pulmonary adenocarcinoma A549 in nude mouse was established. Thirty nude mice were divided into control group，Cisplatin group and XiaoshuiⅡ group. The body weight， food intake， survival time and infiltration of tumor cells in pleural cavity were observed. And the expression of CD44v6，MMP-2，MMP-9，TIMP-1，TIMP-2 in tumor tissue were examinedusing the method of immunohistochemistry.
Results: In Cisplatin group， there were CR 9 case， PR 6 case and NC 5 case and the remission rate was 75%. While in XiaoshuiⅡ group they were 7，7，6 and 70% respectively. XiaoshuiⅡ and Cisplatin could improve patient's QoL level. In Cisplatin group it was 5 mark but in XiaoshuiⅡ group it was 17 (p<0.05). The mean survival time in Cisplatin group was 139 days and the median time was 134 whereas those in XiaoshuiⅡ group were 171，170 respectively. There was remarkable difference between two groups (p<0.05). The result of survival rate by multiple factor analysis showed that MMP-9，MMP-2，CD44，remission rate and QoL had effects on the survival time and the relative risk were therapeutic method，MMP-2，MMP-9，QoL and CD44v6. by uniwariate analysis After treating，CD44v6，IL-2，IFN-γand the activity of NK cell and T cell subset increased while MMP-2，MMP-9 and SIL-2R decreased in XiaoshuiⅡ group. But in the Cisplatin group CD44v6，IL-2，IFN-γ，MMP-9，SIL-2R and the activity of NK cell and T cell subset decreased after treating.
In the animal experiment，the median time in XiaoshuiⅡ groups， which was 43 days，was obviously longer than 36 days in the Cisplatin group. The infiltration of tumor cells in pleural cavity reduced in XiaoshuiⅡ group and there was remarkable difference to the control group. The expression of CD44v6，MMP-9，MMP-2 reduced and TIMP-1， TIMP-2 increased after XiaoshuiⅡ treating.
Conclusion: XiaoshuiⅡ used externally is effective to treat malignant pleural effusion. It can improve the patient's QoL and prolong the survival time. The mechanisms of XiaoshuiⅡ treating malignant pleural effusion partly are: (1) activating immune system to promote pleural adhesions and reduce the development of pleural effusion， (2) suppressing the expression of tumor Adhesiveness molecul CD44v6 and keeping the balance between TIMPs and MMPs to decrease the metastasis of tumor.
消水II号外敷是导师李佩文教授根据祖国医学“内病外治”的理论和多年来治疗癌性积液的经验组成的中药外治复方，通过动物实验证明腹水中有较高活性成分含量，可延长H22腹水小鼠生存期，诱导细胞凋亡，对腹水临床疗效较好，而且应用方便，毒副作用小，药源广，经济实惠，患者乐于接受。我们在以前消水II号外敷治疗腹水的临床及实验研究的基础上，继续探讨消水II号外敷对胸水的临床疗效及其机制，观察消水II号外敷对非小细胞肺癌恶性胸水的疗效及其对晚期癌症患者治疗中生活质量、生存期和胸水生化指标的动态化关系，进一步阐述中医药治疗晚期肺癌并发症胸水的疗效特点和作用机理。
方法：临床部分：（1）将40例肺癌胸水患者随机分为消水II号外敷组和顺铂胸腔灌注组，每组各20例。消水II号外敷组将药物外敷在患侧胸壁，每天更换一次。连续治疗4个星期。顺铂胸腔灌注组用顺铂，每周一次，每次40mg，用40ml生理盐水溶解，尽量抽取胸水，然后注射胸腔，连用4次。按照疗效评价标准，观察两组患者胸水治疗缓解率。（2）采用国际通用的肺癌生活质量问卷（EORTC QLQ-C30-L13）调查，对生活质量状况进行评价。（3）观察两组之间的生存期。（4）治疗前和治疗后常规采取胸水，采用ELISA双抗夹心法检测胸水中CD44v6、MMP-2、MMP-9、IL-2、IFN-γ、sIL-2R及胸水中NK活性、CD4+/CD8+比值。（4）采用前进法多因素分析治疗后MMP-9、MMP-2、CD44v6、缓解率、QOL、CD4+/CD8+的变化对生存率的影响。并分析独立因素对生存的影响。
结果：临床方面：（1）两组治疗后DDP组完全缓解（CR）9例；部分缓解（PR）6例；无效（NC）5例，缓解率（CR+PR）为75%，消水II号组完全缓解（CR）7例；部分缓解（PR）7例；无效（NC）6例，缓解率（CR+PR）为70%。两组无明显差异。显示消水II号可达到和DDP胸腔内注射同等样效果。（2）对生活质量状况的评价结果：消水II号组和顺铂治疗组都可以增加评分，消水II号组平均提高17分，而DDP组平均提高5分，经t检验两组有显著差异（p<0.05）。（3）延长生存期，DDP治疗组平均生存时间139天，中位生存时间为134天，消水II号组平均生存时间171天，中位生存时间为170天，两组之间有明显的差异（p<0.05）。（4）影响生存率的多因素分析结果：MMP-9、MMP-2、CD44v6、缓解率、QOL对生存时间都有影响，对生存影响的风险比率顺序为治疗方式、MMP-2、MMP-9、生活质量、CD44v6。（5）胸水中免疫指标和粘附分子的变化：治疗后消水II号外敷组胸水中CD44v6、IL-2、IFN-γ水平有所升高、NK、T细胞亚群活性增高。胸水中MMP-2、MMP-9、sIL-2R的水平下降。顺铂治疗组CD44v6、IL-2、IFN-γ、sIL-2R、MMP-9水平降低、NK、T细胞亚群活性降低。
实验方面：（1）消水II号外敷后肿瘤细胞在胸腔里的浸润程度明显减轻，与基质对照组比有差异显著。（2）延长小鼠生存期：DDP组中位生存时间为36天，消水II号组为43天。消水II号组中位生存时间明显长于顺铂治疗组（p<0.01）。说明消水II号外敷治疗能延长模型小鼠的生存时间。（3）免疫组化法观察结果显示：消水II号外敷后瘤体组织中CD44v6、MMP-9、MMP-2表达减弱，与基质对照组比有显著差异（p<0.05）。TIMP-1、TIMP-2的表达增强，与基质对照组比有显著差异（p<0.05）。
结论：（1）消水II号外敷治疗恶性胸水的缓解率和顺铂相当。（2）消水II号外敷治疗恶性胸水可以提高患者的生活质量。缓解临床症状，而且对机体无毒副作用，应用方便、患者乐于接受。（3）通过稳定病灶，有效延长肿瘤患者的生存期。多因素分析影响生存率的因素显示：治疗方式、缓解情况、MMP-2对生存影响最大。提示消水II号治疗后缓解的重要性，对缓解情况、生活质量、MMP-2、MMP-9的单因素分析显示，都为独立预后因素。（4）提高胸水中CD44v6、IL-2、IFN-γ水平、增加NK活性。降低胸水中MMP-2、MMP-9、sIL-2R的水平。提示消水II号外敷能活化免疫细胞，促进胸膜粘连，减少胸水的渗出。（5）抑制肿瘤细胞粘附分子CD44v6的表达、保持TIMPs和MMPs之间的平衡，降低肿瘤细胞的恶性程度，从而抑制了肿瘤的转移。
Purpose: malignant pleural effusion (MPE) was the common complication of carcinoma. Pulmonary carcinoma was the most common carcinoma complicated by pleural effusion， especially adenocarcinoma，which complication rate was 37%. Pleural effusion indicated the disease had diffused locally or widely. So，treating the pleural effusion actively was the effective method to prolong the survival time and improve the quality of life.
XiaoshuiⅡ was exterior compound according to the principle of " treating the inner diseases by exterior medicine" of TCM. And there had been some animal experiments and clinical trials studying to its effect. Basing on those studies，the effect and mechanism of XiaoshuiⅡ were researched in this study.
Methods: clinical trial: forty lung cancer patients with pleural effusion were divided into two groups，XiaoshuiⅡ group and Cisplatin (DDP) group. The patients of XiaoshuiⅡ group were given XiaoshuiⅡ external used on the thoracic wall for 4 weeks， changed every 2 days. Cisplatin，40mg solved in 40ml saline，was injected into the thoracic cavities of the patients in Cisplatin group every week for 4 weeks. The quality of life (QoL) and survival time were evaluated. In addition，ELISA was used to examine the CD44v6， MMP-2，MMP-9，IL-2，IFN-γ，sIL-2R，activity of NK and T subset in pleural effusion respectively before and after treatment. The effect of survival rate related with the change of MMP-9，MMP-2，CD44v6， remission rate， QoL and CD4/CD8 was analysed by COX analysis.
Animal experiment: at first，the pleura metastasis model of human pulmonary adenocarcinoma A549 in nude mouse was established. Thirty nude mice were divided into control group，Cisplatin group and XiaoshuiⅡ group. The body weight， food intake， survival time and infiltration of tumor cells in pleural cavity were observed. And the expression of CD44v6，MMP-2，MMP-9，TIMP-1，TIMP-2 in tumor tissue were examined
Results: In Cisplatin group， there were CR 9 case， PR 6 case and NC 5 case and the remission rate was 75%. While in XiaoshuiⅡ group they were 7，7，6 and 70% respectively. XiaoshuiⅡ and Cisplatin could improve patient's QoL level. In Cisplatin group it was 5 mark but in XiaoshuiⅡ group it was 17 (p<0.05). The mean survival time in Cisplatin group was 139 days and the median time was 134 whereas those in XiaoshuiⅡ group were 171，170 respectively. There was remarkable difference between two groups (p<0.05). The result of survival rate by multiple factor analysis showed that MMP-9，MMP-2，CD44，remission rate and QoL had effects on the survival time and the relative risk were therapeutic method，MMP-2，MMP-9，QoL and CD44v6. by uniwariate analysis After treating，CD44v6，IL-2，IFN-γand the activity of NK cell and T cell subset increased while MMP-2，MMP-9 and SIL-2R decreased in XiaoshuiⅡ group. But in the Cisplatin group CD44v6，IL-2，IFN-γ，MMP-9，SIL-2R and the activity of NK cell and T cell subset decreased after treating.
In the animal experiment，the median time in XiaoshuiⅡ groups， which was 43 days，was obviously longer than 36 days in the Cisplatin group. The infiltration of tumor cells in pleural cavity reduced in XiaoshuiⅡ group and there was remarkable difference to the control group. The expression of CD44v6，MMP-9，MMP-2 reduced and TIMP-1， TIMP-2 increased after XiaoshuiⅡ treating.
Conclusion: XiaoshuiⅡ used externally is effective to treat malignant pleural effusion. It can improve the patient's QoL and prolong the survival time. The mechanisms of XiaoshuiⅡ treating malignant pleural effusion partly are: (1) activating immune system to promote pleural adhesions and reduce the development of pleural effusion， (2) suppressing the expression of tumor Adhesiveness molecul CD44v6 and keeping the balance between TIMPs and MMPs to decrease the metastasis of tumor.
引文
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