Suppression of 9L gliosarcoma growth by copper depletion with copper-deficient diet and D-penicillamine

Trace element such as Cu and Zn have important chemical and biological properties. Recently, tissue Cu and Zn concentrations have been correlated with prognosis in selected malignancies. In addition, depletion of trace metals has suppressive effects on tumor growth in experimental rat models. We measured tissue levels of Cu and Zn and investigated the inhibitory effects on tumor growth in a rat brain tumor model by the Cu-depletion. 9L gliosarcoma cells were injected subcutaneously in 24 anesthetized 5 week old male Fischer-344 rats. Control animals (n = 12) were given a normal diet throughout the experiment and hypocupremic rats (n = 12) were given a Cu-deficient diet beginning 3 weeks before and after tumor implantation, and administered 2 mg of D-Penicillamine peri os., once daily, 3 days before and after implantation. At the time of sacrifice, samples were taken to measure tumor weights. To determine tissue Cu and Zn levels, atomic absorption spectrophotometry was used. Cu, Zn and Cu/Zn ratio were significantly higher in control tumors than brain tissues. Cu levels and Cu/Zn ratio were significantly lower in hypocupremic tumors than those in control tumors. Zn levels in hypocupremic tumors were significantly higher than control tumors. Our study indicated that Cu depletion by a Cu-deficient and D-Penicillamine reduced Cu concentration and Cu/Zn ratio in a tumor model with reduction of tumor weight. A metabolic approach that restricts Cu to alter the microenvironment within the cell must become a new horizon of cancer therapy.