臺灣博碩士論文加值系統

化學療法為有效的的癌症治療方法之一。然而，由於化學療法之抗腫瘤效果為非特 異性效果，所以除了抑制癌細胞的生長，也會給正常細胞帶來傷害。因此，化學療法會造 成一些嚴重的副作用如:食慾不好、體重減少、骨髓抑制、免疫抑制以及貧血等副作用。 這些由化學療法所造成的副作用會嚴重影響病人的生活品質甚至導致死亡。因此，如何降 低化學療法所造成的副作用成為近年來備受矚目的研究議題。紅麴 (Monascus) 在中國、 日本及東南亞國家為具有千年使用歷史的傳統食物添加劑。在過去的研究中，紅麴發酵產 物被證實具有改善高脂血症、抗發炎、抑制癌症及降低放射線治療副作用等功效。本篇研 究使用 5-fluorouracil (5 FU) 合併 oxaliplatin (為目前用於治療晚期結直腸癌之一線化療藥 物)作為皮下誘導 CT26 大腸癌小鼠產生化學療法副作用之誘導藥物。在給予化療藥物誘 導副作用的同時，給予 10 天治療組別小鼠紅麴發酵山藥萃取物 Ankascin 568-R 以探討其 對化療副作用之改善效果。結果顯示，腹腔注射總劑量 100 mg/kg BW 5 FU 合併 3 mg/kg BW oxaliplatin 可成功誘導小鼠產生食慾減退、體重減少、骨髓細胞減少、骨髓形成血球 前驅細胞能力 (colony-forming unit-granulocyte macrophage, CFU-GM 和 colony-forming unit- erythrocyte, CFU-E) 降低、骨髓白血球系列細胞減少及骨髓紅血球系列細胞成熟反應抑制。 此外，化療處理也會造成血液循環中的血球減少，證明化療藥物的施打的確會造成骨髓抑 制、免疫抑制及貧血。在給予小鼠管餵 Ankascin 568-R 後，上述之化療副作用都可得到改 善。除此之外， 本研究也發現給予管餵 500 mg/kg BW Ankascin 568-R 之實驗組與單純給 予化療之組別相比，其腫瘤重量具有顯著下降之情形，顯示 Ankascin 568-R 在腫瘤抑制具 有協同效果。為瞭解 Ankascin 568-R 改善效果的可能機制，我們進行了骨髓細胞週期及脾 臟生長因子 interleukin-1b (IL-1b)、interleukin-6 (IL-6)、interleukin-3 (IL-3) 及 granulocyte colony-stimulating factor (GM-CSF) 之分析。結果發現， Ankascin 568-R 可改善骨髓中因化 療所造成的細胞週期 S 期停滯並且具有提升脾臟中 IL-1b、IL-6、IL-3 及 GM-CSF 濃度之 功效。本研究顯示 Ankascin 568-R 具有進一步開發作為改善化療副作用之食品補充劑或藥物之潛力。

Chemotherapy is one of the effective treatments for cancer. However, it not only inhibits the growth of cancer cells but also brings damage to normal cells due to its non-specific effect. Therefore, severe adverse effects such as poor appetite, body weight reduction, myelosuppression, immunosuppression, anemia, etc. would be resulted. Those side effects of chemotherapy can seriously affect the life quality, and even the mortality of patients. Thence, studies in the reduction of chemotherapeutic side effect became an interesting topic in recent years. Monascus is a traditional food additive that is widely used in China, Japan, and other South East Asia countries for thousands of years. Its fermented products have been proved for their advantages in hypolipidemia, anti-inflammation, cancer suppression, radiotherapeutics’ side effects reduction and other benefits. In this study, 5-fluorouracil (5 FU) with the combination of oxaliplatin (the first-line treatment for advanced colorectal cancer) has been used as the inducer of chemotherapeutic side effects in CT26 colorectal cancer subcutaneously induced mice. Ankascin 568-R, the extract of Monascus fermented dioscorea was fed to the targeted groups of mice for 10 days concurrently in order to evaluate the effect on chemotherapeutic side effects. The results showed intraperitoneal (i.p.) injection of a total dosage 100 mg/kg BW 5 FU and 3 mg/kg BW oxaliplatin could induce chemotherapeutic side effects such as poor appetite and body weight reduction in chemotherapy only group. Moreover, the cellularity, colony-forming unit-granulocyte macrophage (CFU-GM), colony-forming unit-erythrocyte (CFU-E), and leukocytes lineage cells, erythroid lineage cells maturation in bone marrow was down regulated, and additionally the circulating blood cells reduction were found in chemotherapy only group indicated the causes of myelosuppression, immunosuppression, and anemia by chemotherapy. The oral administration of Ankascin 568-R limited those side effects of chemotherapy. In addition, the synergetic effect of Ankascin 568-R on cancer suppression was also shown in the results while 500 mg/kg BW oral administration of Ankascin 568-R can significantly reduce tumor weight comparing to chemotherapy only group. To understand the possible mechanism of the effects of Ankascin 568- R, we underwent the cell cycle assessment in bone marrow and colony stimulating factors (IL-1b, IL-6, IL-3, and GM-CSF) in spleen. Those results showed Ankascin 568-R could ameliorate the S phase cell cycle arrest by chemotherapy in bone marrow and upregulated the level of IL-1b, IL-6, IL-3 and GM-CSF in spleen. This study indicated Ankascin 568-R would possibly be a favorable candidate in food supplement or drug development for chemotherapeutic side effects moderation.

Contents

謝誌………………………………………………………………………………………I
Abbreviations……………………………………………………………………………III
中文摘要…………………………………………………………………………………VI
Abstract………………………………………………………………………………….VIII
Contents………………………………………………………………………………….X
Figure contents…………………………………………………………………………..XIII
Table contents…………………………………………………………………………...XV
Chapter I. Introduction…………………………………………………………………1
1. The origin of Monascus……………………………………………………………..1
2. Solid substrate fermentation of red mold rice……………………………………….1
3. Secondary metabolites of Monascus and their uses…………………………………1
4. Studies on Monascus purpureus NTU 568 fermented products……………….2
4-1. Effects on hyperlipidemia …………………………………………………….2
4-2. Effects on diabetes ……………………………………………………………3
4-3. Effects on Alzheimer’s disease ……………………………………………….4
4-4. Effects on fatigue ……………………………………………………………..5
4-5. Effects on immunomodulation………………………………………………..5
4-6. Effects on depression………………………………………………………….6
4-7. Effects on cancer………………………………………………………………6
4-8. Effects on side effect of radiotherapy ………………………………………...7
5. Ankascin 568-R……………………………………………………………………...7
6. Chemotherapeutic drugs and their mechanism on tumor suppression…………........8
6-1. 5-Fluorouracil (5 FU)………………………………………………………….8
6-2. Oxaliplatin ……………………………………………………………………11
6-3. The combination of 5 FU and oxaliplatin ……………………………………11
7. The side effects of chemotherapy……………………………………………………14
7-1. Body weight loss ……………………………………………………………...14
7-2. Fatigue………………………………………….……………………………..14
7-3. Myelosuppression …………………………………………………………….14
7-3-1. Cell cycle effect………………………………………………………..15
7-3-2. Hematopoietic cells production effect ………………………………..17
7-3-3. Hematopoietic growth factors ………….……………………………..19
7-4. Liver and kidney pathologic effect……….…………………………………...19
Chapter II. Study aim and experimental architecture ……………………………….22
1. The aim of study……………………………………………………………………..22
2. The flow chart of experiment………………………………………………………..22
Chapter III. Materials and methods…………………………………………………...25
1. Reagents……………………………………………………………………………..25
2. Instruments…………………………………………………………………………..25
3. Solution preparation…………………………………………………………………26
3-1. Phosphate buffer saline (PBS)………………………………………………...26
3-2. Iscove’s Modified Dulbecco’s medium (IMDM)……………………………..26
3-3. Chemotherapeutic agents ……………………………………………………..27
4. Cell culture…………………………………………………………………………..27
5. Animal experiment……………………………...…………………………………...27
5-1. Animal feeding………………………………………………………………..27
5-2. Experiment design…………………………………………………………….28
5-3. Colon cancer subcutaneous induction………………………………………....28
5-4. Chemotherapy side effects induction…………………………………………31
5-5. Sample intervention…………………………………………………………..31
6. Blood sampling…………………………………………………………..………….31
7. Animal sacrifice…………………………………………………………..…………32
8. Bone marrow cell count…………………………………………………………..…32
9. Colony-forming unit-granulocyte, macrophage (CFU-GM) ……………………..…32
10. Colony-forming unit-erythroid (CFU-E) ………………………………………..….33
11. Flow cytometry analysis of CD45, CD71 and TER119…………………………..…33
12. Complete blood count (CBC) test………………………………………..………….33
13. Histopathological analysis………………………………………..………………….34
14. Tumor weight………………………………………..……………………………34
15. Cell cycle……………………………………….……………………………………34
16. Cytokines……………………………………….……………………………………36
17. Statistical analysis……………………………………….…………………………..36
Chapter IV. Results…………………………………………………...………...………37
1. The effect of Ankascin 568-R on body weight ……………………………………..37
2. The effect of Ankascin 568-R on food intake……………………………………….37
3. The effect of Ankascin 568-R on cell count in bone marrow……………………….37
4. The effect of Ankascin 568-R on colony forming units-granulocyte/macrophage and colony forming units-erythrocyte in bone marrow……………………….…….……41
5. The effect of Ankascin 568-R on leukocytes lineage cells in bone marrow ….…….41
6. The effect of Ankascin 568-R on erythroid lineages cells maturation in bone marrow ………………………………………………...………...…………………48
7. The effect of Ankascin 568-R on white blood cell in circulation .…………………48
8. The effect of Ankascin 568-R on red blood cells and anemia index in blood ……...52
9. The effect of Ankascin 568-R on histopathological analysis of liver and kidney…...52
10. The effect of Ankascin 568-R on tumor weight………...………...…………………53
11. The effect of Ankascin 568-R on cell cycle of bone marrow…...………………….53
12. The effect of Ankascin 568-R on cytokines in spleen…...…………………...…...…57
Chapter VI. Discussion and conclusion………………………………………………..64
Chapter VII. Appendix…………………………………………………………………73
Chapter VII. References………………………………………………………………..75


Figure contents

Figure 1. Classification of chemotherapeutic drugs……………………………………...9
Figure 2. The mechanism of 5-fluorouracil on cancer suppression……………………...10
Figure 3. Mechanism of thymidylate synthase inhibited by 5-fluorouracil……………12
Figure 4. DNA adducts formed by oxaliplatin….……………………………………......13
Figure 5. Phases of cell cycle and antineoplastic agents active phase.………………16
Figure 6. Hematopoiesis of bone marrow.………………………………………………..18
Figure 7. Influence of hematopoietic growth factors on blood cell production …20
Figure 8. The framework of this study……………………………………………………23
Figure 9. The experiment design ………………….………….………….………….…...29
Figure 10. The effect of Ankascin 568-R on body weight of colon cancer mice treated with 5 FU and oxaliplatin …………….………….………….………….….....38
Figure 11. The effect of Ankascin 568-R on food intake of colon cancer mice treated with 5 FU and oxaliplatin …………………………………………………………..39
Figure 12. The effect of Ankascin 568-R on bone marrow cells in bone marrow of colon cancer mice treated with 5 FU and oxaliplatin…….…………………...............40
Figure 13. Granulocyte and macrophage colonies by bone marrow cells culture………..42
Figure 14. The effect of Ankascin 568-R on CFU-GM in bone marrow of colon cancer mice treated with 5 FU and oxaliplatin…….…………………….……………43
Figure 15. Erythrocyte colonies by bone marrow cells culture ….………………….…..44
Figure 16. The effect of Ankascin 568-R on CFU-E in bone marrow of colon cancer mice treated with 5 FU and oxaliplatin………………………………………………45
Figure 17. Leukocytes lineage cells (CD45+ cells) in bone marrow....…….......………46
Figure 18. The effect of Ankascin 568-R on leukocytes lineage cells (CD45+ cells) in bone marrow of colon cancer mice treated with 5 FU and oxaliplatin………..47
Figure 19. Erythroid lineages cells (CD71+ and TER119+ cells) in bone marrow……49
Figure 20. The effect of Ankascin 568-R on liver histology of colon cancer mice treated with 5 FU and oxaliplatin.…………………………………………………….54
Figure 21. The effect of Ankascin 568-R on kidney histology of colon cancer mice treated with 5 FU and oxaliplatin.….…………………………………………55
Figure 22. The effect of Ankascin 568-R on tumor weight of colon cancer mice treated with 5 FU and oxaliplatin….…………………………………………………..56
Figure 23. The effect of Ankascin 568-R on cell cycle of bone marrow in colon cancer mice treated with 5 FU and oxaliplatin………………………………………..58
Figure 24. The effect of Ankascin 568-R on interleukin-1 in spleen of colon cancer mice treated with 5 FU and oxaliplatin ……………………………………………...60
Figure 25. The effect of Ankascin 568-R on interleukin-6 in spleen of colon cancer mice treated with 5 FU and oxaliplatin ……………………………………………...61
Figure 26. The effect of Ankascin 568-R on interleukin-3 in spleen of colon cancer mice treated with 5 FU and oxaliplatin ……………………………………………...62
Figure 27. The effect of Ankascin 568-R on granulocyte-macrophage colony-stimulating factor in spleen of colon cancer mice treated with 5 FU and oxaliplatin …………………………………………….………………………63
Figure 28. The effect of Ankascin 568-R on tumor weight and the side effects of chemotherapy………………………………………………………..………..70


Table contents

Table 1. Contents of phosphate buffer saline…………………………………….............26
Table 2. Contents of Iscove’s Modified Dulbecco’s medium……………………............26
Table 3. Animal grouping, treatment, and sample dosages………………………………30
Table 4. Pathological nomenclature and criteria….……………………………………...35
Table 5. The effect of Ankascin 568-R on erythroid lineages cells (CD71+ and TER119+ cells) maturation in bone marrow of colon cancer mice treated with 5 FU and oxaliplatin ……………………………………………………………................50
Table 6. The effect of Ankascin 568-R on complete blood count of colon cancer mice treated with 5 FU and oxaliplatin.………………………………………………51
Table 7. The effect of Ankascin 568-R on cell cycle in bone marrow of colon cancer mice treated with 5 FU and oxaliplatin ……………………………………………….59
Table 8. Comparison of Ankascin 568-R dose on tumor weight and chemotherapeutic side effects ……………………………………………………………………...71
Table 9. Comparison of Ankascin 568-R dose on the possible mechanism ……………..72
Table 10. Pathology – individual micro findings of mice in C, TC, and CHE group…73
Table 11. Pathology – individual micro findings of mice in RA, RB, and RC group…74

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