Gallium nitrate has proven to be extremely potent agent for treating cancer-related hypercalcemia. The mechanism of action of gallium's effect in blocking accelerated bone resorption is unknown. In order to determine whether gallium exerts its effect by acting on bone mineral and/or by acting on bone cells, we will study the in vivo and in vitro effects of gallium salts on hydroxyapatite and bone cells. Gallium salts in doses comparable to those clinically in use will be administered to rats and changes in their bones relative to age-matched controls studied by radiographic, histologic, and chemical analyses. The crystalline properties of the bone mineral in these animals will be examined by x-ray diffraction, density fractionation, and elemental analyses. In vitro, the effect of gallium salts on formation and growth of hydroxyapatite will be followed. Gallium's effect on bone cells will be studied in model bone-cell systems, primary bone-cell cultures, and in the explanted fetal rat bone culture system. Primary cell cultures of avlan osteoclasts and permanent macrophage cell cultures will be studied as models of bone-resorbing cells. Rat osteogenic sarcoma (ROS 17/2) cells will be used as models of osteoblasts. The effect of gallium on cell viability and specific bone cell function will be examined. Through such studies, the mechanism of action of gallium ion will be defined and the most active salts of gallium identified. (W)
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