臺灣博碩士論文加值系統

臨床上，化學治療藥物順氯氨鉑(cisplatin, CDDP)常用於治療固體癌，其引起的腎毒性，常是限制臨床使用的因素之一。本研究利用低劑量CDDP連續投予小鼠，引發腎炎模型，以柴胡及pentoxifylline (PTX)作為預防藥物，評估其在此腎炎之預防效果。
實驗以6週齡雌鼠(BALB/c mice, female)投予不同劑量CDDP (1.25, 2.5, 5 mg/kg/d)及分別投予CDDP 1, 3, 5天探討投予次數引起腎毒性的強度，以確立小鼠CDDP腎炎模型。藉由事先投予柴胡濃縮劑(BR 150, 300, 450 mg/kg/d)及其純成分saikosaponin A, C, D、化學藥品PTX, BR300併用PTX來評估藥物對CDDP引起腎毒性的預防效果。實驗以N-acetyl-b-D-glucosaminidase (NAG)、尿蛋白、urinary creatinine (Ucr.)與BUN評估腎功能；其腎組織以PAS染色觀察病理組織及免疫螢光染色辨別其損傷部位之特異性抗原。
實驗結果顯示，投予不同劑量與次數，以CDDP 5 mg/kg/d連續投予5天損傷最為嚴重，尿液中NAG、尿蛋白與血清中BUN值增加，Ucr.排除降低；組織學觀察到腎小管有明顯的萎縮、脫落與圓柱體沈積，細胞浸潤較少。免疫螢光染色發現投予CDDP會增加TNF-a, cyclin D1的表現。此外，投予3天CDDP即發現腎功能下降，組織學上觀察到腎小管損傷。免疫螢光染色TNF-a, cyclin D1的表現，僅次於5天；但p21的表現在投予1天時最強，3天次之，5天則明顯減弱。
投予藥物中，柴胡及其純成分saikosaponin A, C, D、化學藥品PTX及BR300併用PTX皆可改善腎功能，組織學上腎小管損傷有減輕的情形。藥效評估以BR 300 mg/kg預防效果較好，純成分則以saikosaponin D最佳。

Cisplatin (CDDP) is an effective antineoplastic agent in the treatment of various solid tumors. The clinical utility of CDDP is limited because of its nephrotoxicity. We tried to establish CDDP induced nephrotoxicity in inbred mice and investigated the impact of Bupleuri Radix (BR) and pentoxifylline (PTX) on the model.
BALB/c mice (6 weeks, female) were intraperitoneally administered with 1.25, 2.5, 5 mg/kg/d of CDDP for 5 days (on day 1 to day 5) to determine the experimental dose. Then, CDDP 5mg/kg/d were administered intraperitoneally to determine the relationship between the injection times (on day 1, 3, 5) and the degree of nephrotoxicity.
In the second experiment, CDDP (5 mg/kg/d) was given to mice on day 1 to day 5. The mice were administered orally with Bupleuri Radix extract (BR) (150, 300, 450 mg/kg/d), saikosaponin A, C, D, PTX, BR300 combined with PTX once daily for 10 days (on day -5 to day 5). The control group was treated with distilled water.
Urinary N-acetyl-b-D-glucosaminidase (NAG), urinary protein, urinary creatinine (Ucr.) and blood urea nitrogen (BUN) were determined. Renal tissues were served to histological examination (PAS stain and immunofluorescence staining). The antibodies including TNF-a, p21, cyclin D1 was chosen to recognize the specific antigens, which deposited in injury sites.
The results showed that animals administered with 5 mg/kg/d of CDDP for 5 days having the most severe injury. Elevation of NAG, urinary protein, BUN and decrease of Ucr were observed. The histological examination showed tubular atrophy, existence of cast and a little interstitial infiltration.
Immunofluorescent study revealed CDDP increased the deposition of TNF-a, cyclin D1 in kidneys. Besides, deterioration of kidney function and pathologic alterations were observed on day 3. The deposition of TNF-a, cyclin D1 on day 3 were increased maximally to day 5 gradually. The expression of p21 increased maximally on day 1, but decreased on day 5.
The mice administered orally with BR300, saikosaponin A, C, D, PTX and BR300 combined with PTX ameliorated kidney damage.
BR300 showed the strongest protective effect against CDDP induced nephrotoxicity among the BR groups. Saikosaponin D showed the strongest protective effect among pure compound groups.

目錄…………………………………………………………………I
圖目錄…………………………………………………………………i
表目錄…………………………………………………………………iii
縮寫表…………………………………………………………………iv
中文摘要…………………………………………………………………1
英文摘要…………………………………………………………………3
第一章 緒言……………………………………………………………5
第二章 文獻回顧………………………………………………………8
第一節 順氯氨鉑(Cisplatin)的作用機轉及臨床使用……………8
第二節 Cisplatin引起腎毒性的機轉與臨床表徵………………12
第三節 細胞週期(Cell cycle)的調控……………………………14
第四節 柴胡及柴胡皂苷……………………………………………21
第五節 Pentoxifylline…………………………………………26
第三章 研究目的………………………………………………………29
第四章 材料與方法……………………………………………………30
第一節 不同劑量CDDP對BALB/c小鼠引起腎毒性的探討…30
1.1 實驗動物………………………………………………30
1.2 實驗設計………………………………………………30
1.3尿液收集………………………………………………30
1.4 動物犧牲法、血液及組織切片製作…………………31
1.5 NAG、尿蛋白、creatinine的含量測定………………31
1.6 血清中BUN值的含量測定…………………………32
1.7 Periodoic Acid Schiff’s stain (PAS)組織染色…………32
1.8組織損傷程度的量化…………………………………33
1.9 免疫螢光染色(Immunofluorescence)…………………33
1.10統計方法……………………………………………34
第二節 CDDP投予次數對BALB/c小鼠引起腎毒性的探討…36
2.1 實驗動物………………………………………………36
2.2 實驗設計………………………………………………36
2.3尿液收集………………………………………………36
2.4 動物犧牲法、血液及組織切片製作…………………36
2.5 NAG、尿蛋白、creatinine的含量測定………………36
2.6 血清中BUN值的含量測定…………………………36
2.7 Periodoic Acid Schiff’s stain (PAS)組織染色…………36
2.8組織損傷程度的量化…………………………………36
2.9 免疫螢光染色(Immunofluorescence)…………………36
2.10統計方法……………………………………………36
第三節 柴胡濃縮劑在CDDP引起腎炎模型的藥效評估………38
3.1 實驗動物……………………………………………38
3.2 實驗藥物………………………………………………38
3.3柴胡濃縮劑在此腎炎模型之實驗設計………………38
3.4尿液收集………………………………………………38
3.5 動物犧牲法、血液及組織切片製作…………………38
3.6 NAG、尿蛋白、creatinine的含量測定………………38
3.7 血清中BUN值的含量測定…………………………38
3.8 Periodoic Acid Schiff’s stain (PAS)組織染色…………39
3.9組織損傷程度的量化…………………………………39
3.10 免疫螢光染色(Immunofluorescence)………………39
3.11統計方法……………………………………………39
第四節 各種預防藥物在CDDP引起腎炎模型的藥效評估……41
4.1 實驗動物………………………………………………41
4.2 實驗藥物………………………………………………41
4.3 各種預防藥物在此腎炎模型之實驗設計……………41
4.4 尿液收集………………………………………………41
4.5 動物犧牲法、血液及組織切片製作…………………41
4.6 NAG、尿蛋白、creatinine的含量測定……………41
4.7 血清中BUN值的含量測定…………………………42
4.8 Periodoic Acid Schiff’s stain (PAS)組織染色…………42
4.9組織損傷程度的量化…………………………………42
4.10 免疫螢光染色(Immunofluorescence)………………42
4.11統計方法…………………………………………… 42
第五章 結果……………………………………………………………44
第一節 不同劑量CDDP對BALB/c小鼠引起腎毒性的探討…44
1.1 尿液NAG、尿蛋白、creatinine的含量分析………44
1.2 血清中BUN值的含量分析…………………………45
1.3 組織病理PAS染色……………………………………45
1.4 組織損傷量化分析…………………………………45
1.5免疫螢光染色…………………………………………46
1.5-1 TNF-之表現……………………………………46
1.5-2 p21之表現……………………………………46
1.5-3 Cyclin D1之表現………………………………46
第二節 CDDP投予次數對BALB/c小鼠引起腎毒性的探討…56
2.1 NAG、尿蛋白、creatinine的含量分析…………………56
2.2 血清中BUN值的含量分析…………………………56
2.3 組織病理PAS染色……………………………………56
2.4 組織損傷量化分析………………………………….57
2.5免疫螢光染色…………………………………………57
2.5-1 TNF-之表現……………………………………57
2.5-2 p21之表現……………………………………58
2.5-3 Cyclin D1之表現………………………………58
第三節 柴胡濃縮劑在CDDP引起腎炎模型的藥效評估………67
3.1 NAG、尿蛋白、creatinine的含量分析…………………67
3.2 血清中BUN值的含量分析…………………………68
3.3 組織病理PAS染色……………………………………68
3.4 組織損傷量化分析………………………………….68
3.5免疫螢光染色…………………………………………69
3.5-1 TNF-之表現……………………………………69
3.5-2 p21之表現……………………………………69
3.5-3 Cyclin D1之表現………………………………70
第四節 各種預防藥物在CDDP引起腎炎模型的藥效評估……79
4.1 NAG、尿蛋白、creatinine的含量分析……………79
4.2 血清中BUN值的含量分析…………………………80
4.3 組織病理PAS染色……………………………………80
4.4 組織損傷量化分析…………………………………81
4.5免疫螢光染色…………………………………………81
4.5-1 TNF-之表現……………………………………81
4.5-2 p21之表現……………………………………81
4.5-3 Cyclin D1之表現………………………………82
第六章 討論……………………………………………………………93
第一節 不同劑量CDDP對BALB/c小鼠引起腎毒性的探討…93
第二節 CDDP投予次數對BALB/c小鼠引起腎毒性的探討…95
第三節 柴胡濃縮劑在CDDP引起腎炎模型的藥效評估………97
第四節 各種預防藥物在CDDP引起腎炎模型的藥效評估……98
第七章 結論.…………………………………………………………100
參考文獻……………………………………………………………102

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