指導教授：李繼忠臺灣大學：臨床動物醫學研究所黃鈞奕Huang, Chun-YiChun-YiHuang2014-11-302018-07-092014-11-302018-07-092014http://ntur.lib.ntu.edu.tw//handle/246246/264397鐘擺式化療，又稱為節拍器式化學治療，是一種不同於以往傳統最大耐受劑量的化療方式，以低劑量、定期、很短的時間內重複的給藥，有如鐘擺的規律。此治療方式被認為是以腫瘤新生血管內皮為標的，即對附近供給腫瘤營養的新生血管造成抑制，使腫瘤無法得到營養達到縮小或減緩生長的效果，而且具有專一性，對正常組織較不具傷害性。以此篇研究目的為評估以合併低劑量3-4 mg/m2 chlorambucil與標準劑量0.3mg/kg piroxicam的治療策略，在犬隻癌症上的治療成效與毒性評估，並同時檢測血液中調節型T細胞的量評估調節型T細胞在鐘擺治療中扮演的腳色。 共21隻患犬納入本次研究，平均中位無病時間為140天，平均中位存活時間為261天。在有巨觀腫瘤在身上的患犬，整體有效率約20%，而約有一半的患犬能夠維持在穩定病程。研究發現，當身上沒有巨觀腫瘤的病患、治療前沒有遠端轉移、較低的臨床分級都有明顯延長的存活時間。就毒性而言，有38%的患犬有出現與治療相關的副作用，大部分都局限在輕微的腸胃道症狀如噁心、嘔吐、下痢，症狀多可自行緩解不需額外治療，有一隻患犬治療過程中出現血中肌酐酸(Creatinine)濃度上升的現象，當給藥頻率延長至兩天一次便能回復到正常。在調節型T細胞的平均百分比與總數中，發現在治療有效或穩定的患犬，在28天的序列測量中可以發現明顯的降低趨勢，代表鐘擺治療確實能夠透過調節免疫來達到抑制腫瘤的效果。 總體而言，鐘擺式chlorambucil與piroxicam的合併治療，對於多種的犬隻癌症有不錯的抗癌效果而且沒有嚴重副作用，而對於微觀腫瘤的病患，鐘擺治療更可以提供不錯的治療效果，相較於巨觀腫瘤，鐘擺式治療以維持病患生活品質與減緩腫瘤生長為主要目的。Metronomic chemotherapy, the low-dose, frequently administered chemotherapy has revealed an important impact on the stabilization of cancer disease. Metronomic chemotherapy has revealed recently as an alternative treatment protocol to slow down cancer progression by its known antiangiogenic effect and modulation of immune status without severe adverse effects. The aim of this study was to evaluate the treatment outcome, tolerability and safety of a combination low-dose chlorambucil at a dosage of 3-4 mg/m2 daily and standard-dose piroxicam at a dosage of 0.3mg/kg in spontaneous canine cancers. In addition, the effects of Treg percentages of peripheral blood had been test to determine the function of immune modulation. 21 dogs were enrolled in the study. The median progression-free interval and the median survival time were 140 days and 261 days. In macroscopic disease dogs, overall remission rate was 20% (two of 10). SD was noted in five of 10 dogs (50%). Microscopic disease, without metastasis at the presentation and low to intermediated clinical stage had a significant longer survival time. All the side effects mostly limited to the grade I-II gastrointestinal signs (anorexia, nausea/vomiting or diarrhea) without any hematological or urological toxicity. Only one dog (5%) had elevated creatinine level during treatment. The protocol was well tolerated without severe adverse effects. By series examination of Treg level, there were significant decreasing in mean percentage and absolute number of regulatory T cell of the 28 -day period for the response or stable dogs. In this study, metronomic chlorambucil with piroxicam revealed an acceptable antitumor effect in many kind of canine cancer without severe adverse effect.誌謝 I 中文摘要 II Abstract III Content V Table contents VII Figure contents VIII Chapter I Introduction 1 1.1. The background of metronomic therapy 1 1.2. Tumor angiogenesis 2 1.3. The mechanism of metronomic therapy 4 1.4. Regulatory T cell 5 1.5. Chlorambucil 6 1.6. Piroxicam 7 Chapter II Literatures review 9 2.1. The efficacy of previous studies of metronomic therapy in canine cancer 9 2.2. Adverse events of metronomic therapy 11 2.3. The effect of metronomic therapy in immune modulation 12 Chapter III Aim 15 Chapter IV Materials and methods 16 4.1. Study population 16 4.2. Study design 17 4.3. Response evaluation 18 4.4. Toxicity 19 4.5. Regulatory T cell 19 4.6. Statistical analysis 20 Chapter V Result 22 5.1. Patient characteristics 22 5.2. Tumor response 24 5.3. Analysis of progression free interval in treatment group 24 5.4. Analysis of overall survival time in treatment group 25 5.5. Comparison of PFI in control versus treated dogs 26 5.6. Comparison of OST in control versus treated dogs 26 5.7. Toxicity 28 5.8. Regulatory T cell 29 Chapter VI Discussion 30 6.1. Treatment outcome 30 6.3. Dose of chlorambucil 35 6.4. Toxicity 36 6.5. Regulatory T cell 37 6.6. Limitation of this study 39 Chapter VII Conclusion 41 Tables and Figures 43 References 711154917 bytesapplication/pdf論文公開時間：2016/08/26論文使用權限：同意有償授權(權利金給回饋學校)鐘擺式化療低劑量化療調節型T細胞[SDGs]SDG3thesishttp://ntur.lib.ntu.edu.tw/bitstream/246246/264397/1/ntu-103-R00643001-1.pdf