The effects of fungal-derived high molecular weight chitosan (HMWC) on the prevention of 5-fluorouracil (5-FU)-induced side-effects were studied in a sarcoma-bearing mice model. 5-FU (12.5mg/kg) was gargled into the mice with or without HMWC (25, 75, and 150mg/kg) every 12 h for consecutive 8 or 16 days in different experiments. The HMWC (25—150 mg/kg) exerted no toxicity and did not interfere with the anti-tumor activity of 5-FU on sarcoma-bearing mice. HMWC in a higher dose (150 mg/kg) partially protected 5-FU-induced cytotoxicity on peripheral leukocytes, lymphocytes, and bone marrow CD-19 positive cells. HMWC reversed the 5-FU suppression of intestine sucrase activity and attenuated the 5-FU-induced diarrhea. Bone marrow cells micronucleus and DNA comet assays demonstrated that HMWC significantly reversed 5-FU-induced genome toxicity to marrow cells. These results suggested that fungal-derived HMWC attenuated the 5-FU-induced bone marrow and gastrointestinal toxicity, and has the potential for clinical applications in the future.
Heidelberger, C. , Chaudhuri, N.K. , Danneberg , P. , Mooren, D. , Griesbach, L. , Duschinsky, R. , Schnitzer, R.J. , Pleven, E. and Scheiner, J. (1957). Fluorinated Pyrimidines, A New Class of Tumour-inhibitory Compounds , Nature, 179: 663-666.
2.
Longley, D.B. , Harkin, D.P. and Johnston, P.G. (2003). 5-Fluorouracil: Mechanisms of Action and Clinical Strategies, Nat . Rev. Cancer, 3: 330-338.
3.
Pinedo, H.M. and Peters, G.F. (1988). Fluorouracil: Biochemistry and Pharmacology , J. Clin. Oncol., 6: 1653-1664.
4.
Schuetz, J.D. , Wallace, H.J. and Diasio, R.B. (1984). 5-Fluorouracil Incorporation into DNA of CF-1 Mouse Bone Marrow Cells as a Possible Mechanism of Toxicity , Cancer Res., 44: 1358-1363.
5.
Kouchi, Y. , Maeda, Y. , Morinaga, H. and Ohuchida, A. (1996). Immunotoxic Effects of a New Antineoplastic Agent S-1 in Mice-Comparison with S-1, UFT and 5-FU , J. Toxicol. Sci., 21(Suppl 3): 691-701.
6.
Houghton, J.A. , Houghton, P.J. and Wooten, R.S. (1979). Mechanism of Induction of Gastrointestinal Toxicity in the Mouse by 5-Fluorouracil, 5-Fluorouridine, and 5-Fluoro-2'-Deoxyuridine , Cancer Res. , 39: 2406-2413.
7.
Arroyo-Begovich, A. , Carabez-Trejo, A. and Ruiz-Herrera , J. (1978). Composition of the Cell Wall of Entamoeba Invadens Cysts , Arch. Invest. Med., (Mex), 9(Suppl 1): 99-104.
8.
Lopez-Romero, E. and Ruiz-Herrera , J. (1978). Properties of Beta-glucan Synthetase from Saccharomyces cerevisiae , Antonie Van Leeuwenhoek, 44: 329-339.
9.
Kafetzopoulos, D. , Martinou, A. and Bouriotis, V. (1993). Bioconversion of Chitin to Chitosan: Purification and Characterization of Chitin Deacetylase from Mucor rouxii, Proc . Natl. Acad. Sci. USA, 90: 2564-2568.
10.
Huang, Y.C. , Vieira, A. , Yeh, M.K. and Chiang, C.H. (2007). Pulmonary Anti-inflammatory Effects of Chitosan Microparticles Containing Betamethasone , J. Bioact.Compat. Polym., 22: 30-41.
11.
Muzzarelli, R.A. (1997). Human Enzymatic Activities Related to the Therapeutic Administration of Chitin Derivatives, CellMol. Life Sci., 53: 131-140.
12.
Chandy, T. and Sharma, C.P. (1990). Chitosan-As a Biomaterial, Biomater . Artif. Cells Artif. Organs, 18: 1-24.
13.
Bejugam, N.K. , Sou, M. , Uddin , A.N. , Gayakwad, S.G. and D'Souza , M.J. (2008). Effect of Chitosans and Other Excipients on the Permeation of Ketotifen, FITC-Dextran, and Rhodamine 123 through Caco-2 Cells , J. Bioact. Compat. Polym., 23: 187-202.
14.
Jayakumar, R. , Reis, R.L. and Mano, J.F. (2006). Phosphorous Containing Chitosan Beads for Controlled Oral Drug Delivery , J. Bioact.Compat. Polym., 21: 327-340.
15.
Hejazi, R. and Amiji, M. (2003). Chitosan-based Gastrointestinal Delivery Systems , J. Control Release, 89: 151-165.
16.
Ohe, T. (1996). Antigenotoxic Activities of Chitin and Chitosan as Assayed by Sister Chromatid Exchange , Sci. Total Environ., 181: 1-5.
17.
Maeda, Y. and Kimura, Y. (2004). Antitumor Effects of Various Low-molecular-weight Chitosans are due to Increased Natural Killer Activity of Intestinal Intraepithelial Lymphocytes in Sarcoma 180-bearing Mice , J. Nutr., 134: 945-950.
18.
Shibata, Y. , Foster, L.A. , Metzger , W.J. and Myrvik, Q.N. (1997). Alveolar Macrophage Priming by Intravenous Administration of Chitin Particles, Polymers of N-acetyl-D-glucosamine, in Mice , Infect. Immun. , 65: 1734-1741.
19.
Tokoro, A. , Tatewaki, N. , Suzuki, K. , Mikami, T. , Suzuki, S. and Suzuki, M. (1988). Growth-inhibitory Effect of Hexa-N-acetylchitohexaose and Chitohexaose against Meth-A Solid Tumor , Chem. Pharm. Bull. (Tokyo), 36: 784-790.
20.
Murata, J. , Saiki, I. , Makabe, T. , Tsuta, Y. , Tokura, S. and Azuma, I. (1991). Inhibition of Tumor-induced Angiogenesis by Sulfated Chitin Derivatives , Cancer Res., 51: 22-26.
21.
Fujii, S. , Ikenaka, K. , Fukushima, M. and Shirasaka, T. (1978). Effect of Uracil and its Derivatives on Antitumor Activity of 5-Fluorouracil and 1-(2-Tetrahydrofuryl)-5-Fluorouracil , GANN, 69: 763-772.
22.
Caballero, G.A. , Ausman, R.K. and Quebbeman , E.J. (1985). Long-term, Ambulatory, Continuous IV Infusion of 5-FU for the Treatment of Advanced Adenocarcinomas, Cancer Treat . Rep., 69: 13-15.
23.
Al-Helw, A.A. , Al-Angary, A.A. , Mahrous , G.M. and Al-Dardari , M.M. (1998). Preparation and Evaluation of Sustained Release Cross-linked Chitosan Microspheres Containing Phenobarbitone , J. Microencapsul. , 15: 373-382.
24.
Lin, S.Y. , Chan, H.Y. , Shen , F.H. , Chen, M.H. , Wang, Y.J. and Yu , C.K. (2007). Chitosan Prevents the Development of AOM-induced Aberrant Crypt Foci in Mice and Suppressed the Proliferation of AGS Cells by Inhibiting DNA Synthesis , J. Cell Biochem., 100: 1573-1580.
25.
Osborne, C.K. , Coronado, E.B. and Robinson, J.P. (1987). Human Breast Cancer in the Athymic Nude Mouse: Cytostatic Effects of Long-term Antiestrogen Therapy, Eur . J. Cancer Clin. Oncol., 23: 1189-1196.
26.
Yih, L.H. and Lee, T.C. (2000). Arsenite Induces p53 Accumulation Through an ATM-dependent Pathway in Human Fibroblasts . Cancer Res., 60: 6346-6352.
27.
Nagae, Y. , Miyamoto, H. , Suzuki, Y. and Shimizu, H. (1991). Effect of Estrogen on Induction of Micronuclei by Mutagens in Male Mice, Mutat . Res., 263: 21-26.
28.
Kimura, Y. and Okuda, H. (1999). Prevention by Chitosan of Myelotoxicity, Gastrointestinal Toxicity and Immunocompetent Organic Toxicity Induced by 5-Fluorouracil Without Loss of Antitumor Activity in Mice, Jpn . J. Cancer Res., 90: 765-774.
29.
Kimura, Y. , Sawai, N. and Okuda, H. (2001). Antitumour Activity and Adverse Reactions of Combined Treatment with Chitosan and Doxorubicin in Tumour-bearing Mice , J. Pharm. Pharmacol., 53: 1373-1378.
30.
Kimura, Y. , Onoyama, M. , Sera, T. and Okuda, H. (2000). Antitumour Activity and Side Effects of Combined Treatment with Chitosan and Cisplatin in Sarcoma 180-bearing Mice , J. Pharm. Pharmacol., 52: 883-890.
31.
Kato, Y. , Onishi, H. and Machida, Y. (2005). Contribution of Chitosan and its Derivatives to Cancer Chemotherapy , In Vivo, 19: 301-310.
32.
George, M. and Abraham, T.E. (2006). Polyionic Hydrocolloids for the Intestinal Delivery of Protein Drugs: Alginate and Chitosan - A Review , J. Control Release, 114: 1-14.
