Lectin ATL-104 in amelioration of intestinal damage caused by 5-fluorouracil in rats

George Grant, Michelle Duncan, N Fish

Research output: Contribution to journalArticle

Abstract

Background: Chemotherapy and radiotherapy can damage normal cells in the alimentary tract, leading to epithelial loss and ulceration (mucositis). In vivo, plant lectins stimulate gut epithelial growth. The potential of lectin ATL-104 to ameliorate gut damage caused by chemotherapy was investigated in a rat model. Methods: Rats (3–5/group) were given ATL-104 orally (200 mg/kg) or saline once daily for 1, 2 or 3d, then 5-fluorouracil (5FU, 150 mg/kg, once, ip) on day 4. At 1, 2, 3 and 4d post-5FU, animals were euthanased and small intestine samples collected for histological evaluation. Results were analysed using ANOVA and multiple comparison tests. Results: 5FU: In saline-treated controls, 5FU caused rapid loss of crypt epithelial cells and collapse of villi. Few dividing cells were detectable at 2d. The intestinal sub-epithelial myofibroblast sheath (ISEMF) was also disrupted. The dividing cell population re-established by 4d, but ISEMF did not. Regenerating crypts and villi remained disorganised. Villus heights (151± 8µm, [p0.001]) and intestinal mass (791± 49mg, [p0.001]) were well below those in non-treated controls (523±67µm; 1142±41mg). ATL-104/5FU: Pre-treatment for 3d with ATL-104 ameliorated the effects of 5FU. Crypt cell loss occurred as with saline/5FU, but was less marked. At 2d post-5FU, micro-crypts (clusters of dividing, goblet and Paneth cells enclosed in a myofibroblast sheath) were present throughout the gut. These were sites of organised re-growth. At 4d, villus height (372±27µm, [p0.01]), structure and intestinal mass (1064±42mg, [p0.03]) were returning to normal (523±67µm, 1142±41mg). ATL-104 given for only 1 or 2d also ameliorated the effects of 5FU on the gut, although less effectively than 3d of treatment. ATL-104 had to be given at 1d prior to 5FU. Little or no protection was evident if this dose was omitted. Conclusions: Pre-treatment of rats with ATL-104 limited intestinal damage caused by 5FU and aided restoration of gut structure. ATL-104 is thus a possible treatment for mucositis. Acknowledgement: MD supported by Alizyme TL, GG by Scottish Government Rural and Environmental Research and Analysis Directorate.



Original languageEnglish
Pages (from-to)20513-20513
Number of pages1
JournalJournal of Clinical Oncology
Volume26
Issue number15(S)
Publication statusPublished - May 2008

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Lectins
Fluorouracil
Myofibroblasts
Mucositis
Paneth Cells
Plant Lectins
Drug Therapy
Goblet Cells
Growth
Small Intestine
Analysis of Variance
Radiotherapy
Epithelial Cells

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Lectin ATL-104 in amelioration of intestinal damage caused by 5-fluorouracil in rats. / Grant, George; Duncan, Michelle; Fish, N.

In: Journal of Clinical Oncology, Vol. 26, No. 15(S), 05.2008, p. 20513-20513.

Research output: Contribution to journalArticle

Grant, G, Duncan, M & Fish, N 2008, 'Lectin ATL-104 in amelioration of intestinal damage caused by 5-fluorouracil in rats', Journal of Clinical Oncology, vol. 26, no. 15(S), pp. 20513-20513.
Grant, George ; Duncan, Michelle ; Fish, N. / Lectin ATL-104 in amelioration of intestinal damage caused by 5-fluorouracil in rats. In: Journal of Clinical Oncology. 2008 ; Vol. 26, No. 15(S). pp. 20513-20513.
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abstract = "Background: Chemotherapy and radiotherapy can damage normal cells in the alimentary tract, leading to epithelial loss and ulceration (mucositis). In vivo, plant lectins stimulate gut epithelial growth. The potential of lectin ATL-104 to ameliorate gut damage caused by chemotherapy was investigated in a rat model. Methods: Rats (3–5/group) were given ATL-104 orally (200 mg/kg) or saline once daily for 1, 2 or 3d, then 5-fluorouracil (5FU, 150 mg/kg, once, ip) on day 4. At 1, 2, 3 and 4d post-5FU, animals were euthanased and small intestine samples collected for histological evaluation. Results were analysed using ANOVA and multiple comparison tests. Results: 5FU: In saline-treated controls, 5FU caused rapid loss of crypt epithelial cells and collapse of villi. Few dividing cells were detectable at 2d. The intestinal sub-epithelial myofibroblast sheath (ISEMF) was also disrupted. The dividing cell population re-established by 4d, but ISEMF did not. Regenerating crypts and villi remained disorganised. Villus heights (151± 8µm, [p0.001]) and intestinal mass (791± 49mg, [p0.001]) were well below those in non-treated controls (523±67µm; 1142±41mg). ATL-104/5FU: Pre-treatment for 3d with ATL-104 ameliorated the effects of 5FU. Crypt cell loss occurred as with saline/5FU, but was less marked. At 2d post-5FU, micro-crypts (clusters of dividing, goblet and Paneth cells enclosed in a myofibroblast sheath) were present throughout the gut. These were sites of organised re-growth. At 4d, villus height (372±27µm, [p0.01]), structure and intestinal mass (1064±42mg, [p0.03]) were returning to normal (523±67µm, 1142±41mg). ATL-104 given for only 1 or 2d also ameliorated the effects of 5FU on the gut, although less effectively than 3d of treatment. ATL-104 had to be given at 1d prior to 5FU. Little or no protection was evident if this dose was omitted. Conclusions: Pre-treatment of rats with ATL-104 limited intestinal damage caused by 5FU and aided restoration of gut structure. ATL-104 is thus a possible treatment for mucositis. Acknowledgement: MD supported by Alizyme TL, GG by Scottish Government Rural and Environmental Research and Analysis Directorate.",
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AU - Duncan, Michelle

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N2 - Background: Chemotherapy and radiotherapy can damage normal cells in the alimentary tract, leading to epithelial loss and ulceration (mucositis). In vivo, plant lectins stimulate gut epithelial growth. The potential of lectin ATL-104 to ameliorate gut damage caused by chemotherapy was investigated in a rat model. Methods: Rats (3–5/group) were given ATL-104 orally (200 mg/kg) or saline once daily for 1, 2 or 3d, then 5-fluorouracil (5FU, 150 mg/kg, once, ip) on day 4. At 1, 2, 3 and 4d post-5FU, animals were euthanased and small intestine samples collected for histological evaluation. Results were analysed using ANOVA and multiple comparison tests. Results: 5FU: In saline-treated controls, 5FU caused rapid loss of crypt epithelial cells and collapse of villi. Few dividing cells were detectable at 2d. The intestinal sub-epithelial myofibroblast sheath (ISEMF) was also disrupted. The dividing cell population re-established by 4d, but ISEMF did not. Regenerating crypts and villi remained disorganised. Villus heights (151± 8µm, [p0.001]) and intestinal mass (791± 49mg, [p0.001]) were well below those in non-treated controls (523±67µm; 1142±41mg). ATL-104/5FU: Pre-treatment for 3d with ATL-104 ameliorated the effects of 5FU. Crypt cell loss occurred as with saline/5FU, but was less marked. At 2d post-5FU, micro-crypts (clusters of dividing, goblet and Paneth cells enclosed in a myofibroblast sheath) were present throughout the gut. These were sites of organised re-growth. At 4d, villus height (372±27µm, [p0.01]), structure and intestinal mass (1064±42mg, [p0.03]) were returning to normal (523±67µm, 1142±41mg). ATL-104 given for only 1 or 2d also ameliorated the effects of 5FU on the gut, although less effectively than 3d of treatment. ATL-104 had to be given at 1d prior to 5FU. Little or no protection was evident if this dose was omitted. Conclusions: Pre-treatment of rats with ATL-104 limited intestinal damage caused by 5FU and aided restoration of gut structure. ATL-104 is thus a possible treatment for mucositis. Acknowledgement: MD supported by Alizyme TL, GG by Scottish Government Rural and Environmental Research and Analysis Directorate.

AB - Background: Chemotherapy and radiotherapy can damage normal cells in the alimentary tract, leading to epithelial loss and ulceration (mucositis). In vivo, plant lectins stimulate gut epithelial growth. The potential of lectin ATL-104 to ameliorate gut damage caused by chemotherapy was investigated in a rat model. Methods: Rats (3–5/group) were given ATL-104 orally (200 mg/kg) or saline once daily for 1, 2 or 3d, then 5-fluorouracil (5FU, 150 mg/kg, once, ip) on day 4. At 1, 2, 3 and 4d post-5FU, animals were euthanased and small intestine samples collected for histological evaluation. Results were analysed using ANOVA and multiple comparison tests. Results: 5FU: In saline-treated controls, 5FU caused rapid loss of crypt epithelial cells and collapse of villi. Few dividing cells were detectable at 2d. The intestinal sub-epithelial myofibroblast sheath (ISEMF) was also disrupted. The dividing cell population re-established by 4d, but ISEMF did not. Regenerating crypts and villi remained disorganised. Villus heights (151± 8µm, [p0.001]) and intestinal mass (791± 49mg, [p0.001]) were well below those in non-treated controls (523±67µm; 1142±41mg). ATL-104/5FU: Pre-treatment for 3d with ATL-104 ameliorated the effects of 5FU. Crypt cell loss occurred as with saline/5FU, but was less marked. At 2d post-5FU, micro-crypts (clusters of dividing, goblet and Paneth cells enclosed in a myofibroblast sheath) were present throughout the gut. These were sites of organised re-growth. At 4d, villus height (372±27µm, [p0.01]), structure and intestinal mass (1064±42mg, [p0.03]) were returning to normal (523±67µm, 1142±41mg). ATL-104 given for only 1 or 2d also ameliorated the effects of 5FU on the gut, although less effectively than 3d of treatment. ATL-104 had to be given at 1d prior to 5FU. Little or no protection was evident if this dose was omitted. Conclusions: Pre-treatment of rats with ATL-104 limited intestinal damage caused by 5FU and aided restoration of gut structure. ATL-104 is thus a possible treatment for mucositis. Acknowledgement: MD supported by Alizyme TL, GG by Scottish Government Rural and Environmental Research and Analysis Directorate.

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