Comparison of lowering copper levels with tetrathiomolybdate and zinc on mouse tumor and doxorubicin models.
Tetrathiomolybdate (TM), presumably by lowering copper levels and availability, has shown excellent efficacy in animal models of cancer and models of injury that produce fibrotic or inflammatory damage in lung, heart, and liver. Trials in human patients are underway. If the efficacy of TM is indeed through lowering copper levels, other anticopper drugs should be equally efficacious. Zinc is an anticopper drug, with proven efficacy in Wilson's disease, a disease of copper toxicity. In this study, the efficacy of zinc is compared with TM on a mouse tumor model and on the doxorubicin model of heart damage, and it is hypothesized that when copper availability is lowered to an equivalent extent, the 2 drugs would show equivalent efficacy. No effect is found of zinc on inhibiting growth of a tumor that is markedly inhibited by TM, and zinc is found to be less effective than TM in inhibiting cardiac damage from doxorubicin. This study shows that TM's mechanism of action in protecting against doxorubicin toxicity is because of its anticopper effects, as copper supplementation eliminated the protective effect of TM. It is also hypothesized that the differences between TM and zinc may be caused by TM's mechanism of action in which it binds copper already in the body, whereas zinc does not.
Hou
Guoqing
G
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Mich 48109-0543, USA.
Dick
Robert
R
Zeng
Chunhua
C
Brewer
George J
GJ
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D002570:Ceruloplasmin / Q000032:analysis; D003300:Copper / Q000494:pharmacology*; D003402:Creatine Kinase / Q000097:blood; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity*; D004336:Drug Antagonism; D006321:Heart / Q000187:drug effects*; D007322:Instillation, Drug; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008982:Molybdenum / Q000008:administration & dosage / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D019210:Troponin I / Q000097:blood; D015032:Zinc / Q000008:administration & dosage / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D019210:Troponin I; D003300:Copper; D004317:Doxorubicin; D008982:Molybdenum; C020809:tetrathiomolybdate; D007770:L-Lactate Dehydrogenase; D002570:Ceruloplasmin; D003402:Creatine Kinase; D015032:Zinc