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JNCI Journal of the National Cancer Institute 1999 91(4):354-359; doi:10.1093/jnci/91.4.354
© 1999 by Oxford University Press
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Journal of the National Cancer Institute, Vol. 91, No. 4, 354-359, February 17, 1999
© 1999 Oxford University Press

ARTICLES

Influence of Tangeretin on Tamoxifen's Therapeutic Benefit in Mammary Cancer

Marc E. Bracke, Herman T. Depypere, Tom Boterberg, Veerle L. Van Marck, Krist'l M. Vennekens, Eric Vanluchene, Margareta Nuytinck, Rudolphe Serreyn, Marc M. Mareel

Affiliations of authors: M. E. Bracke, T. Boterberg, V. L. Van Marck, K. M. Vennekens, M. M. Mareel (Department of Radiotherapy, Nuclear Medicine and Experimental Cancerology), H. T. Depypere, R. Serreyn (Department of Gynaecological Oncology), University Hospital, Gent, Belgium; E. Vanluchene, M. Nuytinck, Laboratory M. Nuytinck, Evergem, Belgium.

Correspondence to: Marc E. Bracke, M.D., Ph.D., Department of Radiotherapy, Nuclear Medicine and Experimental Cancerology, University Hospital, De Pintelaan 185, B-9000 Gent, Belgium (e-mail: marc1.bracke{at}rug.ac.be).

BACKGROUND: Tamoxifen and the citrus flavonoid tangeretin exhibit similar inhibitory effects on the growth and invasive properties of human mammary cancer cells in vitro; furthermore, the two agents have displayed additive effects in vitro. In this study, we examined whether tangeretin would enhance tamoxifen's therapeutic benefit in vivo.METHODS: Female nude mice (n = 80) were inoculated subcutaneously with human MCF-7/6 mammary adenocarcinoma cells. Groups of 20 mice were treated orally by adding the following substances to their drinking water: tamoxifen (3 x 10-5 M), tangeretin (1 x 10-4 M), tamoxifen plus tangeretin (3 x 10-5 M plus 1 x 10-4 M), or solvent. RESULTS AND CONCLUSIONS: Oral treatment of mice with tamoxifen resulted in a statistically significant inhibition of tumor growth compared with solvent treatment (two-sided P = .001). Treatment with tangeretin did not inhibit tumor growth, and addition of this compound to drinking water with tamoxifen completely neutralized tamoxifen's inhibitory effect. The median survival time of tumor-bearing mice treated with tamoxifen plus tangeretin was reduced in comparison with that of mice treated with tamoxifen alone (14 versus 56 weeks; two-sided P = .002). Tangeretin (1 x 10-6 M or higher) inhibited the cytolytic effect of murine natural killer cells on MCF-7/6 cells in vitro, which may explain why tamoxifen-induced inhibition of tumor growth in mice is abolished when tangeretin is present in drinking water. IMPLICATIONS: We describe an in vivo model to study potential interference of dietary compounds, such as flavonoids, with tamoxifen, which could lead to reduced efficacy of adjuvant therapy. In our study, the tumor growth-inhibiting effect of oral tamoxifen was reversed upon addition of tangeretin to the diet. Our data argue against excessive consumption of tangeretin-added products and supplements by patients with mammary cancer during tamoxifen treatment.


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