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Clinical Cancer Research Vol. 6, 1-10, January 2000
© 2000 American Association for Cancer Research

Advances in Brief

Treatment of Metastatic Cancer with Tetrathiomolybdate, an Anticopper, Antiangiogenic Agent: Phase I Study1

George J. Brewer, Robert D. Dick, Damanjit K. Grover, Virginia LeClaire, Michael Tseng, Max Wicha, Kenneth Pienta, Bruce G. Redman, Thierry Jahan, Vernon K. Sondak, Myla Strawderman, Gerald LeCarpentier and Sofia D. Merajver2

Departments of Human Genetics [G. J. B., R. D. D.], Internal Medicine [G. J. B., V. L., M. T., M. W., K. P., B. G. R., S. D. M.], Surgery [K. P., V. K. S.], and Radiology [G. L.], Clinical Research Center [D. K. G.], and Comprehensive Cancer Center [V. L., M. T., M. W., K. P., B. G. R., V. K. S., M. S., S. D. M.], University of Michigan Health System, Ann Arbor, Michigan 48109, and Department of Internal Medicine, University of California at San Francisco, San Francisco, California 94115 [T. J.]

Preclinical and in vitro studies have determined that copper is an important cofactor for angiogenesis. Tetrathiomolybdate (TM) was developed as an effective anticopper therapy for the initial treatment of Wilson’s disease, an autosomal recessive disorder that leads to abnormal copper accumulation. Given the potency and uniqueness of the anticopper action of TM and its lack of toxicity, we hypothesized that TM would be a suitable agent to achieve and maintain mild copper deficiency to impair neovascularization in metastatic solid tumors. Following preclinical work that showed efficacy for this anticopper approach in mouse tumor models, we carried out a Phase I clinical trial in 18 patients with metastatic cancer who were enrolled at three dose levels of oral TM (90, 105, and 120 mg/day) administered in six divided doses with and in-between meals. Serum ceruloplasmin (Cp) was used as a surrogate marker for total body copper. Because anemia is the first clinical sign of copper deficiency, the goal of the study was to reduce Cp to 20% of baseline value without reducing hematocrit below 80% of baseline. Cp is a reliable and sensitive measure of copper status, and TM was nontoxic when Cp was reduced to 15–20% of baseline. The level III dose of TM (120 mg/day) was effective in reaching the target Cp without added toxicity. TM-induced mild copper deficiency achieved stable disease in five of six patients who were copper deficient at the target range for at least 90 days.




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