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      Modulation of N-methyl- N-nitrosourea induced mammary tumors in Sprague–Dawley rats by combination of lysine, proline, arginine, ascorbic acid and green tea extract

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          Abstract

          Introduction

          The limited ability of current treatments to control metastasis and the proposed antitumor properties of specific nutrients prompted us to examine the effect of a specific formulation (nutrient supplement [NS]) of lysine, proline, arginine, ascorbic acid, and green tea extract in vivo on the development of N-methyl- N-nitrosourea (MNU)-induced mammary tumors in rats.

          Methods

          A single intraperitoneal dose of MNU was injected into each of 20 female Sprague–Dawley rats (aged 50 days) to induce tumors. Two weeks after MNU treatment, a time by which the animals had recovered from MNU-induced toxicity, the rats were divided into two groups. Rats in group 1 ( n = 10) were fed Purina chow diet, whereas those in group 2 ( n = 10) were fed the same diet supplemented with 0.5% NS. After a further 24 weeks, the rats were killed and tumors were excised and processed.

          Results

          NS reduced the incidence of MNU-induced mammary tumors and the number of tumors by 68.4%, and the tumor burden by 60.5%. The inhibitory effect of NS was also reflected by decreased tumor weight; the tumor weights per rat and per group were decreased by 41% and 78%, respectively. In addition, 30% of the control rats developed ulcerated tumors, in contrast to 10% in the nutrient supplemented rats.

          Conclusion

          These findings suggest that the specific formulation of lysine, proline, arginine, ascorbic acid, and green tea extract tested significantly reduces the incidence and growth of MNU-induced mammary tumors, and therefore has strong potential as a useful therapeutic regimen for inhibiting breast cancer development.

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          Most cited references22

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          Inhibition of growth and induction of apoptosis in human cancer cell lines by tea polyphenols.

          In order to study the biological activities of tea preparations and purified tea polyphenols, their growth inhibitory effects were investigated using four human cancer cell lines. Growth inhibition was measured by [3H]thymidine incorporation after 48 h of treatment. The green tea catechins (-)-epigallocatechin-3-gallate (EGCG) and (-)-epigallocatechin (EGC) displayed strong growth inhibitory effects against lung tumor cell lines H661 and H1299, with estimated IC50 values of 22 microM, but were less effective against lung cancer cell line H441 and colon cancer cell line HT-29 with IC50 values 2- to 3-fold higher. (-)-Epicatechin-3-gallate, had lower activities, and (-)-epicatechin was even less effective. Preparations of green tea polyphenols and theaflavins had higher activities than extracts of green tea and decaffeinated green tea. The results suggest that the growth inhibitory activity of tea extracts is caused by the activities of different tea polyphenols. Exposure of H661 cells to 30 microM EGCG, EGC or theaflavins for 24 h led to the induction of apoptosis as determined by an annexin V apoptosis assay, showing apoptosis indices of 23, 26 and 8%, respectively; with 100 microM of these compounds, the apoptosis indices were 82, 76 and 78%, respectively. Incubation of H661 cells with EGCG also induced a dose-dependent formation of H2O2. Addition of H2O2 to H661 cells caused apoptosis in a manner similar to that caused by EGCG. The EGCG-induced apoptosis in H661 cells was completely inhibited by exogenously added catalase (50 units/ml). These results suggest that tea polyphenol-induced production of H2O2 may mediate apoptosis and that this may contribute to the growth inhibitory activities of tea polyphenols in vitro.
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            Comparative study of human and rat mammary tumorigenesis.

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              Influence of Drinking Green Tea on Breast Cancer Malignancy among Japanese Patients

              Inhibitory effects of green tea on carcinogenesis have been investigated in numerous laboratory studies using (–)‐epigallocatechin gallate (EGCG) or crude green tea extract, and there is also some epidemiologic evidence. Further, EGCG has been reported to inhibit the growth of cancer cells, lung metastasis in an animal model, and urokinase activity. In this study, we first examined the association between consumption of green tea prior to clinical cancer onset and various clinical parameters assessed at surgery among 472 patients with stage I, II, and III breast cancer. We found that increased consumption of green tea was closely associated with decreased numbers of axillary lymph node metastases among premenopausal patients with stage I and II breast cancer and with increased expression of progesterone receptor (PgR) and estrogen receptor (ER) among postmenopausal ones. Since these are potential prognostic factors, we then investigated the prognosis of breast cancer with special reference to consumption of green tea, in a follow‐up study of these patients. We found that increased consumption of green tea was correlated with decreased recurrence of stage I and II breast cancer (P<0.05 for crude disease‐free survival); the recurrence rate was 16.7 or 24.3% among those consuming ≥5 cups or ≥4 cups per day, respectively, in a seven‐year follow‐up of stage I and II breast cancer, and the relative risk of recurrence was 0.564 (95% confidence interval, 0.350–0.911) after adjustment for other lifestyle factors. However, no improvement in prognosis was observed in stage III breast cancer. Our results indicate that increased consumption of green tea prior to clinical cancer onset is significantly associated with improved prognosis of stage I and II breast cancer, and this association may be related to a modifying effect of green tea on the clinical characteristics of the cancer.
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                Author and article information

                Journal
                Breast Cancer Res
                Breast Cancer Research
                BioMed Central (London )
                1465-5411
                1465-542X
                2005
                31 January 2005
                : 7
                : 3
                : R291-R295
                Affiliations
                [1 ]Matthias Rath Research, Cancer Division, Santa Clara, California, USA
                Article
                bcr989
                10.1186/bcr989
                1143570
                15987424
                2c1a6191-d6a4-465b-9d87-ead4b7df8891
                Copyright © 2005 Roomi et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is cited.

                History
                : 29 September 2004
                : 18 November 2004
                : 25 November 2004
                : 20 December 2004
                Categories
                Research Article

                Oncology & Radiotherapy
                mammary tumors,antitumor effect,n-methyl-n-nitrosourea,sprague–dawley rats

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