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Clinical observation and experimental study of the efficacy of a Chinese medicine formula on malignant tumour bone metastasis diseases.

机译：中药配方治疗恶性肿瘤骨转移疾病的临床观察和实验研究。

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摘要

Malignant tumours leading to high mortality and morbidity are a serious threat to human health. It is the leading cause of death in China. In Hong Kong, there are over 20 thousand new cancer cases and more than 1100 people die due to cancers every year.;Malignant tumour is characterized by early metastasis. Among them 37 to 80 (depending on which type of cancer) patients show tendency of bone metastasis. Bone metastasis is usually accompanied by various complications, such as severe pain, pathological bone fracture, hypercalcemia, and bone marrow suppression, which can substantially affect the quality of life of the patients. Thus, the prevention and treatment of bone metastasis in cancer is an issue worth pursuing.;At present, there is no cure for bone metastasis. The current goals in patient care are to palliate pain, prevent pathological bone fracture and increase the strength and function of bone, so as to extend the life expectancy and maintain a good quality of life. Bisphosphonate treatment is the currently standard therapy of bone metastasis and is commonly used by physicians; it alleviates the tumour-induced hypercalcemia in 90% of patients and reduces the metastatic bone pain in 50% of patients. Moreover, it also prevents the pathological fracture of the affected bones. However, while effective, bisphosphonate injections are very costly, though its oral formulation is less expensive it is also less efficacious, and causes gastrointestinal discomfort. Furthermore, prolonged use of bisphosphonate treatment may lead to certain adverse effects, including hypocalcemia. These factors will prohibit the longterm use of such medication as it can negatively affect the treatment outcome.;Chinese medicine has long been used to treat cancers. Its advantages reside in its holistic properties, which bring palliative, corrective and convalescing functions against damage caused by radiotherapy, chemotherapy and surgery. These features position Chinese medicines as the adjuvant to orthodox cancer treatment. During the late stage of tumour development, when standard therapy is no longer effective, Chinese medicine plays a critical role as an integrated therapy. Searching for a safe, inexpensive and effective Chinese medicine preparation suitable for prolonged use as adjunct therapy in late cancer cases is of paramount importance.;In accordance with Chinese medicine, bone metastasis can be categorized into "bone tumour" "bone erosion" "bone wilting" "bone necrosis" and "bone impediment". The main cause of bone metastasis is twofold: cancer toxicity, and in Chinese medicine theory, the kidney governs the bone marrow, if the kidney is not functioning in balance, then the bone will become weak. Cancer toxicity is the "pathogenic cause" to skeletal metastases, while kidney weakness decreases the body defence against the cancer. A vicious cycle ensues when cancer and kidney deficiency and bone weakness occurs simultaneously coincidently and worsens the conditions.;Based on the above-described understanding of Chinese medicine and bone metastasis, supplementing the kidney and strengthening bone could be the basic principle for the treatment of bone metastasis using Chinese medicine. In view of this theory, and in addition to the clinical observation and a thorough search of the available literature, we selected relevant kidney-tonifying Chinese herbs, namely (Fructus Ligustri Lucidi), (Rhizoma Drynariae), (Herba Epimedii), (Psoralea Corylifolia) and wide-spectrum anticancer herbs (Herba Hedyotidis Diffusae) for the preparation of a combined formula--BBYNG.;Study objectives. To elucidate the efficacy and some pharmacological aspects of BBYNG in regard to the treatment of bone metastasis through clinical observation and different laboratory experiments. This study would be of significant reference value to the disease-oriented drug formulation and application, mechanistic study and research methodology of the treatment of bone metastasis using Chinese medicines.;The research study is composed of three parts, the clinical study, in vivo animal study and in vitro study on tumour cell lines. The research methods used are as follows: Clinical study . The study was designed as a randomized, parallel-group comparison between BBYNG formula and Bisphosphonate. The patients who meet the inclusion/exclusion criteria were randomly assigned to receive either BBYNG granules, which was prepared by a GMP manufacturer, or Clodronic acid. The treatment period was 6 months (24 weeks). For both groups, various clinical parameters such as body functions, blood examinations, bone density (BMD) assessment, X-ray examinations, pain intensity and quality of life were evaluated and compared.;In vivo animal study. A well-established animal model for breast cancer was used to evaluate and compare the pharmacological effects of BBYNG formula and Clodronic acid, as shown by different indicators such as tumour progression, animal's mobility, survival time, bone metastasis-induced fracture intensity and the immunological status of the tumour-bearing mice.;In vitro study on tumour cell lines. The anticancer effects of different concentrations of BBYNG formula and various single components against human breast cancer and lung cancer cell lines were evaluated by cell viability test (MTT assay), cell apoptosis test and invasion suppression test.;The clinical and laboratory experimental results are summarized as below: Clinical results. Both Chinese medicine and Western medicine treated patients showed no significant change in their blood parameters or liver and kidney examinations before and after drug administration; Male subjects on BBYNG, their bone mass density remained stable after 6 months treatment and the subjects on OSTAC showed slightly decreased In females, subjects on BBYNG remained stable, but subjects on OSTAC slightly increased.;Those on BBYNG treatment showed more a stable and satisfactory quality of life than those in the Western medicine-treated group. For the Clodronic acid treatment group, patients generally showed worsened symptoms and quality of life deteriorated. The ECOG index of the BBYNG group was statistically better than that of the Clodronic acid group. Within the 72-week clinical observational period, the mortality of Clodronic acid group is significantly higher that of the BBYNG group. The effects of BBYNG group as presented in relieving the pain-induced influence on patients' emotion, interpersonal relationship and entertainment was more pronounced than that in the Clodronic acid group.;In vivo animal study results. (Tumour growth was slower in the BBYNG treatment group when compared to the OSTAC and control groups, but this was not significantly difference) BBYNG significantly delayed tumour growth in tumour bearing mice, but it did not minimize the tumour size markedly. Moreover, BBNYG did minimize the mobility restriction caused by tumours, reduce the damage to bones, prolong the survival time and enhanced the T lymphocyte immunity.;In vitro study results. BBYNG and the aqueous extracts of its component herbs at very low drug concentrations stimulated the growth of three tumour cell lines tested. When the concentrations were slightly increased, they showed an inhibitory effect on cancer cell proliferation. As the drug concentrations further increased, the extracts showed cytotoxic effects on these tumor cells. At the noncytotoxic dose, the extracts could trigger apoptosis and enhance the caspase-3 activity in all three tumour cell lines. In addition, at this "non toxic" concentration, the extracts markedly inhibited the in vitro invasive property of the 4T1 breast cancer cell lines in our Matrigel invasion model. Thus these in vitro results suggested that BBYNG possess anticancer, invasion-inhibitory and anti-metastatic activities.;Conclusions. (1) As an adjuvant to patients with bone metastases, BBYNG is effective in relieving the metastatic bone pain, improving the quality of life. (2) In the animal model, BBYNG reduced the metastatic bone damage, prolonged the survival and enhanced the T lymphocyte immunity in the tumour-bearing mice. (3) In vitro study on the breast and lung cancer cell lines showed that BYYNG could induce apoptosis and prevent tumour cell invasion. It suggests that BYYNG may restrict tumour growth and development, thus reducing the occurrence of bone metastasis. Based on enormous medical potentials illustrated by the aforementioned findings, BBYNG deserves wider clinical application, large-scale clinical study on its preventive effect against bone metastasis and detailed investigation of its mode(s) of action in the body.
机译：导致高死亡率和高发病率的恶性肿瘤是对人类健康的严重威胁。它是中国死亡的主要原因。在香港，每年有超过2万例新癌症病例，并且有1100多人死于癌症。；恶性肿瘤的特征是早期转移。其中37至80名患者（取决于癌症类型）显示出骨转移的趋势。骨转移通常伴有各种并发症，例如剧烈疼痛，病理性骨折，高钙血症和骨髓抑制，这可能会严重影响患者的生活质量。因此，预防和治疗癌症中的骨转移是一个值得追求的问题。；目前，还没有治愈骨转移的方法。当前患者护理的目标是减轻疼痛，预防病理性骨折并增加骨骼的强度和功能，从而延长预期寿命并维持良好的生活质量。双膦酸盐治疗是目前骨转移的标准疗法，是医师常用的治疗方法。它减轻了90％的患者因肿瘤引起的高钙血症，减轻了50％的患者的转移性骨痛。而且，它还防止了患骨的病理性骨折。然而，尽管有效，双膦酸盐注射剂非常昂贵，尽管其口服制剂较便宜，但疗效也较差，并引起胃肠不适。此外，长时间使用双膦酸盐治疗可能导致某些不良反应，包括低血钙。这些因素将禁止长期使用此类药物，因为它会对治疗结果产生负面影响。中药长期以来一直用于治疗癌症。它的优势在于其整体特性，具有姑息，矫正和恢复功能，可抵抗放射疗法，化学疗法和手术引起的损害。这些特点使中药成为正统癌症治疗的佐剂。在肿瘤发展的后期，当标准疗法不再有效时，中药在综合疗法中起着至关重要的作用。寻找适合长期用于辅助晚期癌症患者的辅助治疗的安全，廉价和有效的中药制剂是至关重要的；根据中医，骨转移可分为“骨肿瘤”，“骨侵蚀”，“骨”枯萎”，“骨坏死”和“骨障碍”。骨转移的主要原因有两个：癌症毒性，在中医理论中，肾脏支配着骨髓，如果肾脏不能保持平衡，骨骼就会变得虚弱。癌症毒性是骨骼转移的“病因”，而肾脏无力则降低了机体抵抗癌症的能力。同时发生癌症和肾脏缺乏症以及骨骼无力并恶化病情时，会形成恶性循环；基于上述对中医和骨转移的理解，补肾壮骨可能是治疗糖尿病的基本原则。中医骨转移。根据这一理论，除了临床观察和对现有文献的全面搜索外，我们还选择了相关的补肾中草药，即（枸杞子），（百香草），（淫羊Epi），（补骨脂） Corylifolia）和广谱抗癌药（Herba Hedyotidis Diffusae）用于制备组合配方-BBYNG。研究目标。通过临床观察和不同的实验室实验来阐明BBYNG在治疗骨转移方面的功效和一些药理学方面。这项研究对以疾病为导向的药物制剂和应用，中药治疗骨转移的机理研究和研究方法具有重要的参考价值。研究包括临床研究，活体动物研究三部分。肿瘤细胞系的研究和体外研究。使用的研究方法如下：临床研究。该研究被设计为BBYNG配方和双膦酸盐之间的随机平行组比较。符合纳入/排除标准的患者被随机分配接受由GMP制造商制备的BBYNG颗粒或氯膦酸。治疗期为6个月（24周）。对于两组，评估并比较了各种临床参数，例如身体功能，血液检查，骨密度（BMD）评估，X射线检查，疼痛强度和生活质量。已建立的乳腺癌动物模型用于评估和比较BBYNG配方和氯膦酸的药理作用，如肿瘤进展，动物活动度等不同指标所显示，存活时间，骨转移引起的骨折强度和荷瘤小鼠的免疫状态。；肿瘤细胞系的体外研究。通过细胞存活力试验（MTT法），细胞凋亡试验和侵袭抑制试验评价了不同浓度的BBYNG配方和各种单一成分对人乳腺癌和肺癌细胞的抗癌作用。总结了临床和实验室实验结果如下：临床结果。中药和西药治疗的患者在给药前后血液参数或肝肾检查均无明显变化。接受BBYNG治疗的男性受试者，经过6个月的治疗，其骨密度保持稳定，而OSTAC组的受试者则略有下降。女性中，接受BBYNG的受试者保持稳定，但接受OSTAC的受试者则略有增加。生活质量高于西药治疗组。对于氯膦酸治疗组，患者通常表现出症状恶化，生活质量恶化。在统计学上，BBYNG组的ECOG指数优于氯膦酸组。在72周的临床观察期内，氯膦酸组的死亡率显着高于BBYNG组。与氯膦酸组相比，BBYNG组在减轻疼痛引起的对患者情绪，人际关系和娱乐的影响方面的效果更为显着。 （与OSTAC组和对照组相比，BBYNG治疗组的肿瘤生长较慢，但这没有显着差异）BBYNG显着延迟了荷瘤小鼠的肿瘤生长，但并未使肿瘤的大小最小化。此外，BBNYG确实最小化了由肿瘤引起的活动性限制，减少了对骨骼的损伤，延长了生存时间并增强了T淋巴细胞的免疫力。 BBYNG及其成分草药的水提取物在非常低的药物浓度下刺激了三种测试的肿瘤细胞系的生长。当浓度稍微增加时，它们显示出对癌细胞增殖的抑制作用。随着药物浓度的进一步增加，提取物对这些肿瘤细胞显示出细胞毒性作用。在无细胞毒性剂量下，提取物可在所有三种肿瘤细胞系中触发凋亡并增强caspase-3活性。此外，在此“无毒”浓度下，提取物显着抑制了我们的Matrigel入侵模型中4T1乳腺癌细胞系的体外入侵特性。因此，这些体外结果表明BBYNG具有抗癌，抑制侵袭和抗转移的活性。 （1）BBYNG作为骨转移患者的佐剂，可有效缓解转移性骨痛，改善生活质量。 （2）在动物模型中，BBYNG减少了荷瘤小鼠的转移性骨损伤，延长了存活时间并增强了T淋巴细胞免疫力。 （3）对乳腺癌和肺癌细胞系的体外研究表明，BYYNG可以诱导细胞凋亡并阻止肿瘤细胞的侵袭。这表明BYYNG可能会限制肿瘤的生长和发展，从而减少骨转移的发生。基于上述发现所显示的巨大医学潜力，BBYNG值得更广泛的临床应用，其对骨转移的预防作用应进行大规模的临床研究，并应对其体内的作用方式进行详细研究。

著录项

  • 作者

    Wu, Ka.;

  • 作者单位

    The Chinese University of Hong Kong (Hong Kong).;

  • 授予单位 The Chinese University of Hong Kong (Hong Kong).;
  • 学科 Biophysics Medical.;Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 2006
  • 页码 324 p.
  • 总页数 324
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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