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Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE 68178,
*
Department of Surgery, Creighton University School of Medicine, Omaha, NE 68131 and
Department of Food Science and Human Nutrition, Iowa State University, Ames, IA 50011
3To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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0.05). The median number of tumors in the control group was 67, and
those in the isoflavone-supplemented groups were 57, 33, 32, and
17, respectively. The last was significantly different from the control
(P 0.05). Dietary supplementation with
isoflavones at 225 µmol/kg, 450 µmol/kg, and 900 µmol/kg also
significantly decreased tumor size (median cross-sectional area and
volume) compared to the control values. We conclude that dietary
supplementation with isoflavones reduces experimental metastasis of
melanoma cells in mice.
KEY WORDS: • mice • genistein • daidzein • melanoma • metastasis
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), prostate (Severson et al. 1989
), uterine (Goodman et al. 1997
), and
gastric cancers (Nagai et al. 1982
) in humans. Dietary
supplementation with soybean protein isolate
(SPI)4
(Hawrylewicz et al. 1991
) or soybean chips
(Barnes et al. 1990
) reduces mammary carcinogenesis in
female rats. Adding autoclaved raw soybean to the diet of male mice
inhibits carcinogenicity of N-nitroso compounds in the liver
and urinary bladder (Mokhtar et al. 1988
). These
protective effects are associated with soy isoflavones, e.g. genistein
and daidzein. Long-term intraperitoneal administration of genistein
and daidzein to young rats (Constantinou et al. 1996
)
and subcutaneous injection of genistein to neonatal rats
(Lamartiniere et al. 1995
) reduce the development of
mammary carcinoma after exposure of the animals to carcinogens. Other
studies showed that soy-derived products have no effect on
tumorigenesis in some animal models (Reddy et al. 1976
).
Soybean is a rich source of dietary isoflavones
(Murphy 1982
). Isoflavones exist in soybean primarily as
conjugated glycosides. Following ingestion, they are hydrolyzed to
aglycones by glycosidases produced by intestinal bacteria. The
conjugates genistin, daidzin, and glycitin and their aglycones,
genistein, daidzein, and glycitein constitute 90–95% of the total soy
isoflavones (Murphy 1982
). It appears that the
unconjugated aglycones are associated with many biological properties
of isoflavones that may be responsible for their anticancer activities.
These include antiestrogenic activity (Folman and Pope 1966
), inhibition of protein tyrosine kinases (Akiyama et al. 1987
), regulation of cell cycle progression and
apoptosis (Kroemer et al. 1995
), and antiangiogenic
activity (Fotsis et al. 1993
).
Metastasis, the spread of malignant cells from a primary
neoplasm to distant organs that results in the development of secondary
tumors, is the most devastating aspect of cancer. Advances in surgical
techniques and adjuvant therapies have proven useful in the treatment
of primary tumors. However, metastasis remains a major cause of poor
prognosis and death in cancer patients. We recently reported that
dietary supplementation with SPI reduces pulmonary metastasis of murine
melanoma cells in mice (Yan et al. 1997
). Connolly et al. (1997)
reported that soybean chips inhibit metastasis of human
mammary carcinoma cells in athymic nude mice. These studies suggest
that dietary soybean is useful in preventing the spread of malignant
cells.
The objective of the present study was to determine whether isoflavones present in SPI reduce metastasis. To accomplish this, the effect of dietary supplementation with isoflavones genistein and daidzein on pulmonary metastasis of melanoma cells was investigated using an intravenous injection model.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The protocol of the present study was reviewed and approved by
the Creighton University Animal Care and Use Committee and complied
with the Guide for the Care and Use of Laboratory Animals
(National Research Council 1985
). Three-week-old male
C57BL/6 mice were purchased from Charles River (Wilmington, MA). Mice
were housed five per box, in wire-topped plastic boxes, in a
pathogen-free room on a 12:12-h light-dark cycle. The
temperature in the room was maintained at 25 ± 1°C. Mice were
given free access to the diet and deionized water and weighed weekly.
Five diets were compared: a basal diet and the basal diet supplemented
with genistein and daidzein (Lancaster, Windham, NH) at 113, 225, 450,
or 900 µmol/kg, which was equivalent to that provided in the diet
containing 2.5, 5, 10 or 20% SPI, respectively (Yan et al. 1997
). The concentration of genistein in
isoflavone-supplemented diets was 83.3, 166.7, 333.3, and 666.7
µmol/kg, respectively, and the concentration of daidzein was 29.5,
59.1, 118.1, and 236.2 µmol/kg, respectively. Glycitein was omitted
from the supplementation because it was not commercially available.
Dietary formulations were based on the AIN-93G standard diet
(Reeves et al. 1993
), except that soybean oil was
replaced with corn oil. Diet components were purchased from ICN (Costa
Mesa, CA). All diets were prepared in our laboratory, and each lot was
stored at 4°C for no longer than 3 wk.
Experimental design.
Ninety mice were fed the basal diet for 2 d before being assigned
to five groups of 18 each. They were then fed the basal diet or one of
the isoflavone-supplemented diets. B16BL6 murine melanoma cells
(Dr. I. J. Fidler, University of Texas, Houston, TX) were cultured
in minimum essential medium with 10% heat-inactivated fetal bovine
serum as described previously (Yan et al. 1997
). The
melanoma cells were collected from monolayer cultures by a brief
trypsinization (0.05% trypsin and 0.53 mmol/L EDTA). The viability of
the cells was determined with trypan blue, and a single cell suspension
was made in serum-free medium. After 2 wk consuming the diets, each
mouse was injected via the lateral tail vein with 0.5 x
105 viable cells in 0.2 mL. To avoid possible changes in
cell viability, melanoma cells were injected into mice within 30 min
after their collection. The order that tumor cells were injected into
mice from different dietary groups was randomized. The mice were then
fed the diets for another 2 wk. One wk before tumor cell injection, six
mice from each group were transferred to metabolic cages, and their
food intake was recorded over 7 d. Urine collected from each group
(n = 6) throughout this week was pooled and
analyzed for isoflavones (Xu et al. 1994
). Isoflavone
intake was calculated on the basis of food intake and the dietary
concentration of isoflavones.
At the end of the experiment, mice were anesthetized using
ketamine (50 mg/kg body weight) and xylazine (5 mg/kg body weight) and
then killed by cervical dislocation. Their lungs were excised and fixed
in 10% phosphate-buffered formalin. The number of pulmonary tumors
was determined by counting visible black foci by using a dissecting
microscope (Yan et al. 1997
). The cross-sectional
area of tumors in randomly selected fields was measured using a
Quantimet 500 image analysis system (Leica Cambridge, Cambridge, UK).
Tumor volume was calculated using the mean of the longest and the
shortest diameters measured and the assumption that tumors were
spherical (Welch et al. 1983
).
Statistical analysis.
Fisher's exact test (Steel and Torrie 1980
) was used to analyze the frequency distribution of the
mice that had 1–15 tumors or >15 tumors. Bartlett's test
(Bartlett, 1937
) for homogeneity of variances revealed
that standard deviations for the mean values of the number of tumors,
tumor cross-sectional area, and tumor volume differed significantly
among the groups (P 0.05). Because ANOVA can
only be used to compare the means of populations with homogeneous
variances, the results were analyzed using the Kruskal-Wallis
nonparametric and Dunn's multiple comparison tests (Kruskal and Wallis 1952
). The data were analyzed using the statistic
program Instat 2.01 for Macintosh. Differences were considered
significant at P 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. There were no measurable isoflavones in urine from mice fed the basal
diet. The urinary excretion of isoflavones (a sum of genistein,
daidzein, and daidzein metabolites equol and
O-desmethylangolensin) was increased in a dose-dependant
manner in mice fed the diet containing isoflavones at 113, 225, 450 or
900 µmol/kg (Table 1)
. One mouse from the control group and one from
the 900 µmol isoflavones/kg group were excluded from the experiment
because their growth was significantly less than all other mice.
|
). Based on the number of lung tumors per mouse, the mice were
placed into one of the two categories: 1) 1–15 tumors and
2) >15 tumors. In the control group, all mice had >15 lung
tumors (Table 2
). By contrast, 89, 83, 72, and 59% of the mice in groups fed the diets
containing isoflavones at 113, 225, 450, and 900 µmol/kg,
respectively, had >15 tumors. The latter two were significantly
different from the control (P 0.05). The median
number of lung tumors in the control group was 67. The median number of
lung tumors reduced in the 900 µmol/kg isoflavone/kg group compared
to the control (P 0.05). The mean number of lung
tumors in mice fed the isoflavone-supplemented diets decreased
relative to the control in a dose-dependent manner.
|
). Dietary supplementation with isoflavones
decreased both variables in a dose-dependent manner. The difference
in tumor cross-sectional area and volume between the control and
the groups supplemented with isoflavones at 225, 450, or 900 µmol/kg
was significant (P 0.01).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Results of
the present study demonstrate that dietary supplementation with
isoflavones at concentrations equivalent to that provided in the SPI
diets decreased the number of lung tumors and the tumor
cross-sectional area and volume compared to the controls. The
dietary isoflavone content was positively correlated with both the
urinary isoflavone concentration and the magnitude of the inhibitory
effect on metastasis. Dietary supplementation with isoflavones up to
900 µmol/kg had no adverse effect on the growth of mice during the
experimental period. These results indicate that isoflavones
effectively reduced pulmonary metastasis of melanoma cells and also
retarded the growth of those tumors that developed in the lungs.
The observations from this study provide the first evidence that
dietary supplementation with isoflavones reduces experimental
metastasis. This is supported by the findings that oral administration
of genistein inhibits lung metastasis of melanoma cells intravenously
injected into mice (Menon et al. 1998
). Interestingly,
they found that daidzein was ineffective in reducing metastasis. In the
present study, the effect of dietary supplementation with either
genistein or daidzein alone was not tested. However, the concentration
of genistein in the experimental diets was threefold greater than that
of daidzein. Thus, the protective effect of dietary isoflavones on
experimental metastasis may be largely attributed to genistein. Whether
daidzein is without an effect is difficult to conclude from the
currently available data. In the study described by Menon et al. (1998)
, injection of 1 x 106 melanoma cells
into mice led to the development of uncountable massive lung tumors in
control and daidzein-treated animals. Thus, they were unable to
determine whether or not daidzein was effective in reducing metastasis.
At present, the mechanism whereby dietary soybean or isoflavones
reduces metastasis remains unknown. The experimental metastasis model
employed in the present study measured the extravasation of melanoma
cells from the cardiovascular system into the interstitum of the lungs.
This requires invasion of the subendothelial basement membrane.
Genistein inhibits the invasion of extracellular matrix by BALB/c
mammary carcinoma cells in vitro (Scholar and Toews 1994
). This may be due to an effect of genistein on cell
adhesion to the extracellular matrix. Genistein is a potent inhibitor
of protein tyrosine kinases (Akiyama et al. 1987
).
Protein tyrosine kinases phosphorylate tyrosine residues on proteins
that participate in signal transduction events, including
integrin-mediated cell adhesion (Hynes 1992
). It was
shown that genistein inhibits epithelial growth factor-stimulated
integrin expression by human breast cancer (Narita et al. 1996
) and esophageal cancer cells (Sato et al. 1996
). Furthermore, genistein inhibits integrin-mediated
cell adhesion by lymphoma cells (Weimar et al. 1997
) and
arterial smooth muscle cells (Hedin et al. 1997
). These
observations suggest that isoflavones could reduce metastasis by
affecting cell adhesion. A second possibility is by reducing protease
activity. Genistein inhibits the secretion of urokinase-type
plasminogen activator and metalloproteinase by LM3 murine mammary tumor
cells (Aguirre Ghiso et al. 1998
). These effects were
also attributed to the inhibition of protein tyrosine kinases. It
should be noted that in these studies genistein was used as a
pharmacological tool to study signal transduction events rather than as
a dietary component. The high concentrations employed are beyond the
level that is achievable in animals consuming a soy-containing
diet. Thus, exposure of cultured cells to isoflavones in vitro is not
comparable to providing animals with soybean- or
isoflavone-supplemented diets. Therefore, caution should be taken
when data from in vitro experiments are used to explain a dietary
effect of soybean or isoflavones in animal studies.
The results of the present study demonstrate that tumor
cross-sectional area and volume of mice fed the isoflavone diets
were significantly reduced compared to those of mice fed the basal
diet. A decrease in tumor size could be due to prolonged retention of
tumor cells in the circulatory system or an inhibition of malignant
cell proliferation after they take up residence in the lungs. Most
circulating B16 melanoma cells rapidly die following their
intravenous injection (Fidler 1970
).
Approximately 1% of the cells survive for 24 h, and one tenth of
them form tumor colonies in the lungs. Therefore, it is unlikely that
retention in the circulation explains the difference in tumor size
between the control and the isoflavone-supplemented groups. Rather,
it is more likely that this difference is due to the inhibition of
mitosis of malignant cells in the lungs. Investigations in our
laboratory designed to determine the effect of dietary isoflavones on
cell proliferation and angiogenesis during the formation of metastatic
tumor will clarify this possibility.
Comparing results of the present study with our previous report on
dietary SPI and experimental metastasis (Yan et al. 1997
), it appears that SPI is more effective in reducing the
number of lung tumors than the isoflavone-equivalent diets. Soybean
contains several potential anticancer components other than
isoflavones, e. g., protease inhibitors (Kennedy 1993
)
and saponins (Koratkar and Rao 1997
). Although these
agents are largely eliminated during the preparation of the SPI, trace
amounts may exist. The SPI also contains phytate that has been shown to
have a tumor-attenuating action in some animal models
(Shamsuddin et al. 1988
). Finally, glycitein, which was
present in the SPI employed in our previous study (Yan et al. 1997
), was not supplemented in the diet in the present study.
Thus, these variations could contribute, at least in part, to the
differences observed in these two studies.
In summary, results of the present study demonstrate that dietary supplementation with isoflavones reduced experimental metastasis of melanoma cells in mice and also inhibited the growth of metastatic tumors that developed in the lungs. We conclude that isoflavones are responsible, at least in part, for the protective effect of dietary soybean on experimental metastasis of melanoma cells in mice.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 This work was supported by the State of
Nebraska Cancer and Smoking-Related Disease Research Program (Grant No.
98–51) and by Hazel Berve Trust Fund.
4 Abbreviations used: SPI, soybean protein
isolate.
Manuscript received November 5, 1998. Revision accepted February 1, 1999.
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REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
1. Aguirre Ghiso J. A., Farias E. F., Alonso D. F., Bal de Kier Joffe E. Secretion of urokinase and metalloproteinase-9 induced by staurosporine is dependent on a tyrosine kinase pathway in mammary tumor cells. Int. J. Cancer 1998;76:362-367[Medline]
2.
Akiyama T., Ishida J., Nakagawa S., Ogawara H., Watanabe S., Itoh N. M., Shibuya M., Fukami Y. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J. Biol. Chem. 1987;262:5592-5595
3. Barnes S., Grubbs C., Setchell K.D.R., Carlson J. Soybeans inhibit mammary tumors in models of breast cancer. Pariza M. eds. Mutagens and Carcinogens in the Diet 1990:239-253 Wiley-Liss New York, NY.
4. Bartlett M. S. Properties of sufficiency and statistical tests. Proc. Roy. Soc. 1937;A160:268-282
5. Connolly J. M., Liu X. H., Rose D. P. Effects of dietary menhaden oil, soy, and a cyclooxygenase inhibitor on human breast cancer cell growth and metastasis in nude mice. Nutr. Cancer 1997;29:48-54[Medline]
6. Constantinou A. I., Mehta R. G., Vaughan A. Inhibition of N-methyl-N-nitrosourea-induced mammary tumors in rats by the soybean isoflavones. Anticancer Res 1996;16:3293-3298[Medline]
7. Fidler I. J. Metastasis: Quantitative analysis of distribution and fate of tumor emboli labeled with 125I-5-iodo-2'-deoxyuridine. J. Natl. Cancer Inst. 1970;45:773-782
8. Folman Y., Pope G. S. The interaction in the immature mouse of potent estrogen with coumesterol, genistein and other utero-vaginotrophic compounds of lower potency. J. Endocrinol. 1966;34:215-225[Medline]
9.
Fotsis T., Pepper M., Adlercreutz H., Fleischmann G., Hase T., Montesano R., Schweigerer L. Genistein, a dietary-derived inhibitor of in vitro angiogenesis. Proc. Natl. Acad. Sci. USA 1993;90:2690-2694
10.
Goodman M. T., Wilkens L. R., Hankin J. H., Lyu L. C., Wu A. H., Kolonel L. N. Association of soy and fiber consumption with the risk of endometrial cancer. Am. J. Epidemiol. 1997;146:294-306
11. Hawrylewicz E. J., Huang H. H., Blair W. H. Dietary soybean isolate and methionine supplementation affect mammary tumor progression in rats. J. Nutr. 1991;121:1693-1698
12.
Hedin U., Thyberg J., Roy J., Dumitrescu A., Tran P. K. Role of tyrosine kinases in extracellular matrix-mediated modulation of arterial smooth muscle cell phenotype. Arterioscler. Thromb. Vasc. Biol. 1997;17:1977-1984
13. Hynes R. O. Integrins: Versatility, modulation, and signaling in cell adhesion. Cell 1992;69:11-25[Medline]
14. Kennedy A. R. Anticarcinogenic effect of protease inhibitors. Troll W. Kennedy A. R. eds. Protease Inhibitors as Cancer Chemopreventive Agents 1993:65-91 Plenum Publishing New York, NY.
15. Koratkar R., Rao A. V. Effect of soya bean saponins on azoxymethane-induced preneoplastic lesions in the colon of mice. Nutr. Cancer 1997;27:206-209[Medline]
16. Kroemer G., Petit P., Zamzami N., Vayssiere J. L., Mignotte B. The biochemistry of programmed cell death. FASEB J 1995;9:1277-1287[Abstract]
17. Kruskal W. H., Wallis W. A. Use of ranks in one-criterion variance analysis. J. Am. Statist. Assoc. 1952;47:583-621
18.
Lamartiniere C. A., Moore J. B., Brown N. M., Thompson R., Hardin M. J., Barnes S. Genistein suppresses mammary cancer in rats. Carcinogenesis 1995;16:2833-2840
19. Lee H. P., Gourley L., Duffy S. W., Esteve J., Day N. E. Dietary effects on breast cancer risk in Singapore. Lancet 1991;337:1197-1200[Medline]
20. Menon L. G., Kuttan R., Nair M. G., Chang Y. C., Kuttan G. Effect of isoflavones genistein and daidzein in the inhibition of lung metastasis in mice induced by B16F-10 melanoma cells. Nutr. Cancer 1998;30:74-77[Medline]
21. Mokhtar N. M., El-Asser A. A., El-Bolkainy M. N., Ibrahim H. A., El-din N. B., Moharram N. Z. Effect of soybean feeding on experimental carcinogenesis-III. Carcinogenicity of nitrite and dibutylamine in mice: A histopathological study. Eur. J. Cancer Clin. Oncol. 1988;24:403-411[Medline]
22. Murphy P. A. Phytoestrogen content of processed soybean products. Food Technol 1982;36:60-64
23. Nagai M., Hashimoto T., Yanagawa H., Yokoyama H., Minowa M. Relationship of diet to the incidence of esophageal and stomach cancer in Japan. Nutr. Cancer 1982;3:257-268[Medline]
24. Narita T., Kawakami-Kimura N., Sato M., Matsuura N., Higashiguchi N., Kannagi R. Alteration of integrins by heparin-binding EGF-like growth factor in human breast cancer cells. Oncology 1996;53:374-381[Medline]
25. National Research Council.(1985)Guide for the Care and Use of Laboratory Animals. Publication no. 85–23 (rev.): National Institutes of Health, Washington DC.
26. Reddy B. S., Narisawa T., Weisburger J. H. Effect of a diet with high levels of protein and fat on colon carcinogenesis in F344 rats treated with 1, 2-methyhydrazin. J. Natl. Cancer Inst. 1976;57:567-569
27. Reeves P. G., Nielsen F. H., Fahey G. C. AIN-93 purified diets for laboratory rodents: Final report of the American Institute of Nutrition Ad Hoc Writing Committee on the reformulation of the AIN-76A rodent diet. J. Nutr. 1993;123:1939-1951
28. Sato M., Narita T., Kawakami-Kimura N., Higashiyama S., Taniguchi N., Akiyama S., Hashimoto T., Manabe T., Kannagi R. Increased expression of integrins by heparin-binding EGF-like growth factor in human esophageal cancer cells. Cancer Lett 1996;102:183-191[Medline]
29. Scholar E. M., Toews M. L. Inhibition of invasion of murine mammary carcinoma cells by the tyrosine kinase inhibitor genistein. Cancer Lett 1994;87:159-162[Medline]
30.
Severson R. K., Nomura A.M.Y., Grove J. S., Stemmermann G. N. A prospective study of demographics, diet, and prostate cancer among men of Japanese ancestry in Hawaii. Cancer Res 1989;49:1857-1860
31.
Shamsuddin A. M., Elsayed A. M., Ullah A. Suppression of large intestine cancer in F344 rats by inositol hexaphosphare. Carcinogenesis 1988;9:577-580
32. Steel R.G.D., Torrie J. H. Enumeration data I: One-way classifications. Principles and Procedures of Statistics: A Biometric Approach 2nd ed. 1980:477-532 McGraw-Hill New York, NY.
33.
Weimar I. S., de Jong D., Muller E. J., Nakamura T., van Gorp J.M.H, de Gast G. C., Gerritsen W. R. Hepatocyte growth factor/scatter factor promotes adhesion of lymphoma cells to extracellular matrix molecules via 
4ß1 and 5ß1 integrins. Blood 1997;89:990-1000
34. Welch D. R., Neri A., Nicolson G. L. Comparison of `spontaneous' and `experimental' metastasis using rat 13762 mammary adenocarcinoma metastatic cell clones. Invasion Metastasis 1983;3:65-80[Medline]
35. Xu X., Wang H. J., Murphy P. A., Cook L., Hendrich S. Daidzein is a more bioavailable soymilk isoflavone than is genistein in adult women. J. Nutr. 1994;124:825-832
36. Yan L., Yee J. A., McGuire M. H., Graef G. A. Effect of dietary supplementation of soybeans on experimental metastasis of melanoma cells in mice. Nutr. Cancer 1997;29:1-6[Medline]
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