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.