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Department of Internal Medicine, Division of Hematology and Oncology [Q. P., L. W. B., G. J. B., S. D. M.], Departments of Pathology [C. G. K.] and Human Genetics [G. J. B.], and Comprehensive Cancer Center [Q. P., L. W. B., C. G. K., S. D. M.], University of Michigan Medical School, Ann Arbor, Michigan 48109

² To whom requests for reprints should be addressed, at University of Michigan Medical School, Department of Internal Medicine, Division of Hematology and Oncology, 1500 East Medical Center Drive, Ann Arbor, MI 48109. E-mail: smerajve{at}umich.edu

Constitutive activation of nuclear factor B is implicated to be a critical survival mechanism used by carcinoma cells to escape apoptosis. Tetrathiomolybdate (TM), a novel copper chelator, exhibits potent antiangiogenic properties, in part, through suppression of the nuclear factor B signaling cascade. In this study, we determined whether TM enhances doxorubicin-induced apoptosis in SUM149 inflammatory breast carcinoma cells. Apoptosis was not observed in these cells after TM treatment. Moreover, SUM149 cells were relatively resistant to doxorubicin-induced apoptosis ranging from 9.9 ± 2.9% to 21.5 ± 2.0% apoptotic cells for 0.1 to 2.5 µM doxorubicin treatment. A greater-than-additive increase (33.8 ± 4.6%, 57.5 ± 5.2%, or 83.7 ± 1.0% apoptosis with TM and 0.1, 0.5, or 2.5 µM doxorubicin, respectively) in apoptosis was observed in cells treated with the combination therapy of TM and doxorubicin. In SUM149 xenografts, TM and doxorubicin significantly retarded tumor growth in comparison with either agent administered alone (P < 0.03). Tumor cell apoptosis in the combination therapy-treated mice was 113.3 ± 20% greater than that in TM-treated mice and 52.4 ± 14.3% greater than that in doxorubicin-treated mice. These results suggest that TM may enhance the rate of pathological complete response when used in combination with an anthracycline in neoadjuvant therapy of breast carcinoma.

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