Copper-lowering therapy with tetrathiomolybdate for cancer and diseases of fibrosis and inflammation†

Abstract

Angiogenesis is required for tumor growth and is a likely Achilles heel for cancer. However, antiangiogenic agents have been somewhat disappointing in cancer therapy, perhaps because they target a single angiogenic factor, and there is much redundancy in angiogenic systems. Copper is required for high levels of angiogenesis, and many angiogenic factors have a requirement for copper. Thus, anticopper drugs offer the possibility of more global inhibition. Our group has developed tetrathiomolybdate (TM) for the initial treatment of neurologic Wilson's disease. Penicillamine makes about 50% of these patients neurologically worse, and many never recover. Only 2 of 55 (3.6%) patients worsened when treated with TM. Because TM exhibited desirable properties of potency, speed, and safety, we studied it as an antiangiogenic agent. We hypothesize that if copper is lowered to midrange, the cellular requirements for copper are met, but angiogenic cytokine signaling is inhibited. TM has shown strong inhibition of cancer growth in five rodent models, encouraging results in a canine study of advanced and metastatic cancer, and encouraging results in a phase 1/2 study of advanced and metastatic cancer in 42 patients. Finally, we have hypothesized that the pathway of fibrosis involving transforming growth factor beta (TGF-β) and connective tissue growth factor is inhibitable by copper-lowering therapy with TM. This pathway is overactive and dysregulated in many diseases of fibrosis. In animal studies, TM has completely inhibited the pulmonary fibrosis induced by bleomycin, the hepatitis induced by concanavalin A, and the cirrhosis induced by carbon tetrachloride. We find that TM inhibits transforming growth factor beta and inflammatory cytokines tumor necrosis factor alpha and interleukin-1-beta. J. Trace Elem. Exp. Med. 16:191–199, 2003. © 2003 Wiley-Liss, Inc.