Carcinogenesis, Vol 18, 761-769, Copyright © 1997 by Oxford University Press
T Tanaka, H Makita, K Kawabata, H Mori, M Kakumoto, K Satoh, A Hara, T Sumida, K Fukutani, T Tanaka and H Ogawa
The modifying effects of flavonoids diosmin and hesperidin during the
initiation and post-initiation phases of oesophageal carcinogenesis
initiated with N-methyl-N-amylnitrosamine (MNAN) were investigated in male
Wistar rats. At 7 weeks of age, all animals except those treated each test
chemical alone and control groups were given weekly intraperitoneal
injections of MNAN (12.5 mg/kg body weight/injection) for 12 weeks to
induce oesophageal neoplasms. For examining the modifying effects of
'initiation' treatment of test compounds, groups of animals were fed the
diets containing 1000 ppm diosmin and 1000 ppm hesperidin, and the diet
containing both compounds (900 ppm diosmin and 100 ppm hesperidin) for 13
weeks, starting 7 days before the MNAN dosing and then switched to the
basal diet. For examining the modifying effects of 'post-initiation'
treatment of these compounds, the groups given MNAN and a basal diet were
switched to the experimental diets containing diosmin, hesperidin or
diosmin combined with hesperidin at 1 week after the stop of MNAN
injection, and maintained on these diets for 7 weeks. The other groups
consisted of rats given test compounds alone or untreated rats. All animals
were necropsied at the termination of the study (week 20) to determine the
incidences of oesophageal neoplasms and preneoplasms, blood polyamine
levels, and cell proliferation activity estimated by 5-bromodeoxyuridine
(BrdU)- labelling index and by morphometric analysis of silver-stained
nucleolar organizer regions' protein (AgNORs). A number of oesophageal
neoplasms developed in rats treated with MNAN alone (75% and 100%
incidences of carcinoma and papilloma, respectively). 'Initiation' feeding
of diosmin significantly decreased the incidence of squamous cell carcinoma
(P < 0.05). Also, 'initiation feeding' of both compounds singly or in
combination caused a significant reduction in the multiplicities of
oesophageal carcinoma and papilloma (diosmin, 78 and 58% reduction;
hesperidin, 70 and 50% reduction; and the combination regimen, 70 and 30%
reduction, P < 0.005). 'Post-initiation' feeding slightly decreased the
multiplicities of these oesophageal neoplasms. Also, these dietary regimens
reduced the multiplicities of preneoplastic lesions (hyperplasia and severe
dysplasia; P < 0.05). There were no pathological alterations in rats
treated with both compounds alone or the combined regimen alone or those in
an untreated control group. Similarly, feeding of these compounds
significantly decreased the expression of cell proliferation biomarkers
(BrdU- labelling index and AgNORs number) of the non-lesional oesophageal
epithelium (P < 0.05). Blood polyamine concentrations were also lowered
in rats given the carcinogen and test compounds, both alone and in
combination, when compared with those of rats given MNAN alone (P <
0.05). These findings suggest that diosmin and hesperidin supplementation,
individually or in combination, is effective in inhibiting the development
of oesophageal cancer induced by MNAN when given during the initiation
phase, and such inhibition might be related to suppression of increased
cell proliferation caused by MNAN in the oesophageal mucosa.
ARTICLES
Modulation of N-methyl-N-amylnitrosamine-induced rat oesophageal tumourigenesis by dietary feeding of diosmin and hesperidin, both alone and in combination
First Department of Pathology, Gifu University School of Medicine, Gifu City, Japan.
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