| 研究生: |
許棠閔 Hsu, Tang-Min |
|---|---|
| 論文名稱: |
真菌幾丁聚醣降低癌症化療藥物副作用
之效果評估及其機制之探討 Study on the Prevention Effects of Chitosan in Cancer Chemotherapy – Induced Adverse Effects and Related Mechanisms |
| 指導教授: |
王應然
Wang, Ying-Jan |
| 學位類別: |
碩士 Master |
| 系所名稱: |
醫學院 - 環境醫學研究所 Department of Environmental and Occupational Health |
| 論文出版年: | 2005 |
| 畢業學年度: | 93 |
| 語文別: | 中文 |
| 論文頁數: | 77 |
| 中文關鍵詞: | 副作用 、5-氟尿嘧啶 、幾丁聚醣 、癌症化學治療 |
| 外文關鍵詞: | 5-Fluorouracil, side effects, Chitosan, Cancer Chemotherapy |
| 相關次數: | 點閱:68 下載:1 |
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癌症化學治療通常被用來對付無法用手術去除的癌細胞,不過在接受癌症化學治療的過程中,會對病人產生不良的副作用,影響病人健康。真菌幾丁聚醣(Chitosan)為真菌類細胞壁中的主要成分。研究發現幾丁聚醣具有許多生物活性作用,如增進免疫功能、保護腸胃道及抑制腫瘤細胞生長等。本研究的目的在探討真菌幾丁聚醣對於癌症化學治療所產生的副作用是否有改善的效果,且不影響癌症化療藥物的抗癌效果,並探討其相關的機制。首先利用動物實驗模式,以骨髓毒性、胃腸毒性、免疫功能作為副作用指標,來評估真菌幾丁聚醣對於癌症化學治療藥物(5-氟尿嘧啶,5-FU) 所引發的副作用是否有改善的效果。小鼠實驗中單獨以5-FU給藥及5-FU合併真菌幾丁聚醣方式給藥,藉由測定腫瘤體積與重量、骨髓中CD 19細胞百分比、血液中白血球與淋巴球數量、小腸蔗糖酶活性、腹瀉發生率、微核試驗及彗星分析來評估抗癌效果、副作用發生情形和相關機轉的探討。研究結果顯示,5-FU合併真菌幾丁聚醣給藥並不影響5-FU抑制癌細胞生長的效果。真菌幾丁聚醣減輕了由5-FU所造成骨髓中CD 19百分比及血液中白血球與淋巴球細胞數量的下降情形。5-FU合併真菌幾丁聚醣可以降低小腸黏膜受到損害及延緩小鼠腹瀉的發生率。在微核測驗與彗星分析結果中顯示出5-FU合併真菌幾丁聚醣減少了5-FU對於正常細胞染色體與DNA的傷害。由實驗結果推論,真菌幾丁聚醣可能經由降低5-FU對於正常細胞之DNA傷害,而改善了5-FU所誘發骨髓毒性、免疫毒性與腸胃毒性之副作用。
Cancer chemotherapy is used to treat tumor cells that can not be removed by surgery. In the process of treatment, however, cancer chemotherapy often induces side effects and reduces health of cancer patients. Chitosan is the main component of the fungi’s cell wall. Chitosan has several biological activities such as immuno-enhancing ability, protection mucosa damage in gastrointestinal track and anti-tumor activity. The purpose of this study was to investigate whether Chitosan could improve the side effects induced by chemotherapeutic agent without loss its anti-tumor ability and their related mechanisms. The study examined the anti-tumor activity and side effects (meylotoxicity, immunotoxicity and gastrointestinal toxicity) of combined treatment of chemotherapeutic drug 5-Fluorouracil (5-FU) and Chitosan in vivo. We measured the weight and volume of tumor, percentage of CD19 in bone marrow, leukocyte number, lymphocyte number, sucrase activity, incidence of diarrhea, micronucleated polychromatic erythrocytes (MNPCE) frequency and Comet assay in mice treated with 5-FU plus Chitosan or 5-FU alone to evaluate the effects of Chitosan on the 5-FU-induced anti-tumor activity and side effects. The results showed that 5-FU plus Chitosan inhibited the tumor growth as well as 5-FU alone. Chitosan improved the reduction of leukocyte number, lymphocyte number and CD19 percentage of bone marrow induced by 5-FU. 5-FU combined with Chitosan reduced the injury of the small intestinal mucosa and delayed the onset of diarrhea in mice. 5-FU combined with Chitosan also decreased MNPCE frequency and DNA damage caused by 5-FU in bone marrow cells. The results demonstrate that Chitosan may improve adverse effects induced by 5-FU through reduction DNA damage of normal cell.
Asano, N., Fujimoto, M., Yazawa, N., Shirasawa, S., Hasegawa, M., Okochi,
H., Tamaki, K., Tedder, TF., Sato, S., 2004. B Lymphocyte signaling
established by the CD19/CD22 loop regulates autoimmunity in the tight-skin
mouse. American Journal of Pathology. 165(2):641-650.
Anonymous., 1984. Nomenclature for clusters of differentiation (CD) of
antigens defined on human leukocyte populations. Bulletin of the World
Health Organization. 62(5):809-811.
Anonymous., 1994. CD antigens 1993: an updated nomenclature for clusters of
differentiation on human cells. IUIS/WHO Subcommittee on CD
Nomenclature. Bulletin of the World Health Organization. 72(5):807-808.
Bradbury, LE., Kansas, GS., Levy, S., Evans, RL., Tedder, TF., 1992. The
CD19/CD21 signal transducing complex of human B lymphocytes includes
the target of antiproliferative antibody-1 and Leu-13 molecules. Journal of
Immunology. 149(9):2841-2850.
Brandt, DS., Chu, E., 1997. Future challenges in the clinical development of
thymidylate synthase inhibitor compounds. Oncology Research.
9(8):403-410.
Chu, E., Callender, MA., Farrell, MP., Schmitz, JC., 2003. Thymidylate
synthase inhibitors as anticancer agents: from bench to bedside. Cancer
Chemotherapy & Pharmacology. 52 Suppl 1:S80-89.
Duschinsky, R., Pleven, E., Heidelberg, C., 1957. The synthesis of
5-fluorinated. Journal of the American Chemical Society. 79: 4559-4560.
Eckhardt, S., 2002. Recent progress in the development of anticancer agents.
Current Medicinal Chemistry - Anti-Cancer Agents. 2(3):419-439.
Fujimoto, M., Poe, JC., Inaoki, M., Tedder, TF., 1998. CD19 regulates B
lymphocyte responses to transmembrane signals. Seminars in Immunology.
10(4):267-277.
Fujii, S., Shimamoto, Y., Ohshimo, H., Imaoka, T., Motoyama, M., Fukushima,
M., Shirasaka, T., 1989. Effects of the plasma concentration of 5-fluorouracil
and the duration of continuous venous infusion of 5-fluorouracil with an
inhibitor of 5-fluorouracil degradation on Yoshida sarcomas in rats. Japanese
Journal of Cancer Research. 80(2):167-172.
Houghton, JA., Houghton, PJ., Wooten, RS., 1979. Mechanism of induction of
gastrointestinal toxicity in the mouse by 5-fluorouracil, 5-fluorouridine, and
5-fluoro-2'-deoxyuridine. Cancer Research. 39(7 Pt 1):2406-2413.
Harrison, DE., Lerner, CP., 1991. Most primitive hematopoietic stem cells are
stimulated to cycle rapidly after treatment with 5-fluorouracil. Blood.
78(5):1237-1240.
Hyeyoung, M., Encarnacion, MR., Dorshkind, K., 2005. Effects of aging on
early B- and T-cell development. Immunological Reviews. 205 (1):7-17.
Hyams, JS., Batrus, CL., Grand, RJ., Sallan, SE., 1982. Cancer chemotherapy-
induced lactose malabsorption in children. Cancer. 49:646–650.
Henderson, L., Wolfreys, A., Fedyk, J., Bourner, C., Windebank, S., 1998. The
ability of the Comet assay to discriminate between genotoxins and
cytotoxins. Mutagenesis. 13(1):89-94.
Heddle, JA., Hite, M., Kirkhart, B., Mavournin, K., MacGregor, JT., Newell,
GW., Salamone, MF., 1983. The induction of micronuclei as a measure of
genotoxicity. A report of the U.S. Environmental Protection Agency
Gene-Tox Program. Mutation Research. 123(1):61-118.
Inomata, A., Horii, I., Suzuki, K., 2002. 5-Fluorouracil-induced intestinal
toxicity: what determines the severity of damage to murine intestinal crypt
epithelia?. Toxicology Letters. 133(2-3):231-240.
Jeuniaux, C., 1964. "Free" chitin and "masked" chitin in invertebrate skeletal
structures. Archives Internationales de Physiologie et de Biochimie.
72(2):329-330.
Kafetzopoulos, D., Martinou, A., Bouriotis, V., 1993. Bioconversion of chitin to
chitosan: purification and characterization of chitin deacetylase from Mucor
rouxii. Proceedings of the National Academy of Sciences of the United States
of America. 90(7):2564-2568.
Kimura, Y., Okuda, H., 1999. Prevention by carp extract of myelotoxicity and
gastrointestinal toxicity induced by 5-fluorouracil without loss of antitumor
activity in mice. Journal of Ethnopharmacology. 68(1-3):39-45.
Kouchi, Y., Maeda, Y., Morinaga, H., Ohuchida, A., 1996. Immunotoxic effects
of a new antineoplastic agent S-1 in mice. Comparison with S-1, UFT and
5-FU. Journal of Toxicological Sciences. 21 Suppl 3:691-701.
Kotsakis, A., Sarra, E., Peraki, M., Koukourakis, M., Apostolaki, S., Souglakos,
J., Mavromanomakis, E., Vlachonikolis, J., Georgoulias, V., 2000.
Docetaxel-induced lymphopenia in patients with solid tumors: a prospective
phenotypic analysis. Cancer. 89(6):1380-1386.
Lowenthal, RM., Eaton, K., 1996. Toxicity of chemotherapy. Hematology –
Oncology Clinics of North America. 10(4):967-990.
Mi, FL., Wong, TB., Shyu, SS., 1997. Sustained-release of oxytertraacyline
from chitosanmicrospheres prepares by interfacial acylation and
sprayhardening methods. Microencapsulation. 14:577-591.
Moore, BB., Moore, TA., Toews, GB., 2001. Role of T- and B-lymphocytes in
pulmonary host defences. European Respiratory Journal. 18(5):846-856.
Nagae, Y., Miyamoto, H., Suzuki, Y., Shimizu, H., 1991. Effect of estrogen on
induction of micronuclei by mutagens in male mice. Mutation Research.
263(1):21-26.
Ohe, T., 1996. Antigenotoxic activities of chitin and chitosan as assayed by
sister chromatid exchange. Science of the Total Environment. 181(1):1-5.
Ohl, L., Bernhardt, G., Pabst, O., Forster, R., 2003. Chemokines as organizers
of primary and secondary lymphoid organs. Seminars in Immunology.
15(5):249-255.
Ohuchida, A., Furukawa, A., Yoshida, J., Watanabe, M., Aruga, F., Miwa, Y.,
Shinkawa, K., Kinae, N., 1992. Micronucleus assays on 5-fluorouracil and
6-mercaptopurine with mouse peripheral blood reticulocytes. Mutation
Research. 278(2-3):139-143.
Ostling, O., Johanson, KJ., 1984. Microelectrophoretic study of radiation
-induced DNA damages in individual mammalian cells. Biochemical &
Biophysical Research Communications. 123(1):291-298.
Pinedo, HM., Peters, GF., 1988. Fluorouracil: biochemistry and pharmacology.
Journal of Clinical Oncology. 6(10):1653-64.
Park, PJ., Je, JY., Kim, SK., 2003. Free radical scavenging activity of
chitooligosaccharides by electron spin resonance spectrometry. J Agric Food
Chem. 51(6):4624-4627.
Pae, HO., Seo, WG., Kim, NY., Oh, GS., Kim, GE., Kim, YH., Kwak, HJ., Yun,
YG., Jun, CD., Chung, HT., 2001. Induction of granulocytic differentiation in
acute promyelocytic leukemia cells (HL-60) by water-soluble chitosan
oligomer. Leukemia Research. 25(4):339-346.
Rydberg, B., Johanson, KJ., 1978. Estimation of DNA strand breaks in single
mammalian cells. In Hanawalt PC, EC, Fox CF (eds): DNA repair
mechanisms. New York: Academic Press: 465-468.
Schmid, W., 1975. The micronucleus test. Mutation Research. 31(1):9-15.
Shibata, Y., Foster, LA., Metzger, WJ., Myrvik, QN., 1997. Alveolar
macrophages priming by intravenous administration of chitin particles,
polymers of N-acetyl-glucosamine, in mice. Infection and Immunity
65:1734-1741.
Stopper, H., Kuhnel, A., Podschun, B., 1994. Combination of the
chemotherapeutic agent 5-fluorouracil with an inhibitor of its catabolism
results in increased micronucleus induction. Biochemical & Biophysical
Research Communications. 203(2):1124-1130.
Sato, S., Ono, N., Steeber, DA., Pisetsky, DS., Tedder, TF., 1996. CD19
regulates B lymphocyte signaling thresholds critical for the development of
B-1 lineage cells and autoimmunity. Journal of Immunology.
157(10):4371-4378.
Singla, AK., Chawla, M., 2001. Chitosan: some pharmaceutical and biological
aspects--an update. Journal of Pharmacy & Pharmacology.
53(8):1047-1067.
Schuetz, JD., Wallace, HJ., Diasio, RB., 1984. 5-Fluorouracil incorporation
into DNA of CF-1 mouse bone marrow cells as a possible mechanism of
toxicity. Cancer Research. 44(4):1358-1363.
Sugimoto, K., Yoshida, M., Yata, T., Higaki, K., Kimura, T., 1998. Evaluation
of poly(vinyl alcohol)-gel spheres containing chitosan as dosage form to
control gastrointestinal transit time of drugs. Biological & Pharmaceutical
Bulletin. 21(11):1202-1206.
Schipper, NG., Varum, KM.,Artursson, P., 1996. Chitosans as absorption
enhancers for poorly absorbable drugs. 1: Influence of molecular weight and
degree of acetylation on drug transport across human intestinal epithelial
(Caco-2) cells. Pharmaceutical Research. 13(11):1686-1692.
Singh, NP., McCoy, MT., Tice, RR., Schneider, EL., 1988. A simple technique
for quantitation of low levels of DNA damage in individual cells.
Experimental Cell Research. 175(1):184-191.
Tedder, TF., Inaoki, M., Sato, S., 1997. The CD19-CD21 complex regulates
signal transduction thresholds governing humoral immunity and
autoimmunity. Immunity. 6(2):107-111.
Tedder, TF., Isaacs, CM., 1989. Isolation of cDNAs encoding the CD19 antigen
of human and mouse B lymphocytes. A new member of the immunoglobulin
superfamily. Journal of Immunology. 143(2):712-717.
Tokoro, A., Kobayashi, M., Tatewaki, N., Suzuki, K., Okawa, Y., Mikami, T.,
Suzuki, S., Suzuki, M., 1989. Protective effect of N-acetyl chitohexaose on
Listeria monocytogenes infection in mice. Microbiology & Immunology.
33(4):357-367.
Tsukada, K., Matsumoto, T., Aizawa, K., Tokoro, A., Naruse, R., Suzuki, S.,
Suzuki, M., 1990. Antimetastatic and growth-inhibitory effects of
N-acetylchitohexaose in mice bearing Lewis lung carcinoma. Japanese
Journal of Cancer Research. 81(3):259-265.
Takano, F., Tanaka, T., Aoi, J., Yahagi, N., Fushiya, S., 2004. Protective effect
of (+)-catechin against 5-fluorouracil-induced myelosuppression in mice.
Toxicology. 201(1-3):133-142.
Tice, RR., Andrews, PW., Hirai, O., Singh, NP., 1991. The single cell gel
(SCG) assay: an electrophoretic technique for the detection of DNA damage
in individual cells. Advances in Experimental Medicine & Biology.
283:157-164.
Yih, LH., Lee, TC., 2000. Arsenite induces p53 accumulation through an
ATM-dependent pathway in human fibroblasts. Cancer Research. 60(22):
6346-6352.
von Ledebur, M., Schmid, W., 1973. The micronucleus test. Methodological
aspects. Mutation Research. 19(1):109-117.
Zhou, A., Matsuura, Y., Okuda, H., 1994. Chitosan augments cytoplytic activity
of mouse lymphocytes. J. Tradit. Med.11:62-64.