Effects of gallium nitrate in nude mice bearing a canine adenocarcinoma (CAC-8) model of humoral hypercalcemia of malignancy

Abstract

Hypercalcemic nude mice bearing a canine adenocarcinoma (CAC‐8) model of humoral hypercalcemia of malignancy (HHM) were treated daily with gallium nitrate (60 mg/kg of elemental gallium subcutaneously (SC) on day 0, followed by 20 mg/kg/day) for 5 days. Gallium nitrate significantly decreased (p < 0.01) serum calcium in tumor‐bearing animals on days 2 and 5 of treatment (mean 13.7 ± 0.7 mg/dl on day 0 versus 11.6 ± 0.3 on day 2 and 12.4 ± 0.5 on day 5). Urinary calcium excretion was decreased (p < 0.05) in the gallium‐treated, tumor‐bearing animals (0.11 ± 0.01 mg calcium/mg creatinine) compared with hypercalcemic tumor‐bearing mice (0.30 ± 0.06). Both nontumor control and tumor‐bearing mice treated with gallium nitrate lost body weight during the treatment period (p < 0.01). Gallium nitrate had no effect on tumor growth. Histomorphometric evaluation of lumbar vertebrae stained for tartrate‐resistant acid phosphatase revealed a significant decrease (p < 0.05) in the number of osteoclasts/mm trabecular bone and perimeter of trabecular bone lined by active osteoblasts (p < 0.01) in the gallium‐treated tumor‐bearing mice compared with tumor‐bearing controls. Osteoclast length (mm) was significantly increased in both the nontumor and tumor‐bearing gallium‐treated animals (p < 0.05) compared with nontumor and tumor‐bearing control mice. Serum tumor necrosis factor α (TNF‐α) levels were increased in tumor‐bearing animals, but gallium nitrate had no effect on circulating levels (not detectable in nontumor control mice versus 82 ± 21 pg/ml in tumor‐bearing mice and 107 ± 12 pg/ml in gallium‐treated tumor‐bearing mice). Concentrations of gallium in bone were undetectable in untreated control mice (<0.00005 μg/g bone), but markedly elevated concentrations were present in gallium‐treated mice (235 ± 6 μg/g bone in nontumor‐bearing and 155 ± 18 in tumor‐bearing). These results indicate that gallium nitrate decreased osteoclastic bone resorption and serum calcium levels in a nude mouse model of HHM.