EFFECTS OF GALLIUM NITRATE IN NUDE-MICE BEARING A CANINE ADENOCARCINOMA (CAC-8) MODEL OF HUMORAL HYPERCALCEMIA OF MALIGNANCY

Hypercalcemic nude mice bearing a canine adenocarcinoma (CAC-8) model of humoral hypercalcemia of malignancy (HHM) were treated daily with g allium nitrate (60 mg/kg of elemental gallium subcutaneously (SC) on d ay 0, followed by 20 mg/kg/day) for 5 days. Gallium nitrate significan tly decreased (p < 0.01) serum calcium in tumor-bearing animals on day s 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-be aring mice treated with gallium nitrate lost body weight during the tr eatment period (p < 0.01). Gallium nitrate had no effect on tumor grow th. Histomorphometric evaluation of lumbar vertebrae stained for tartr ate-resistant acid phosphatase revealed a significant decrease (p < 0. 05) in the number of osteoclasts/mm trabecular bone and perimeter of t rabecular bone lined by active osteoblasts (p < 0.01) in the gallium-t reated tumor-bearing mice compared with tumor-bearing controls. Osteoc last length (mm) was significantly increased in both the nontumor and tumor-bearing gallium-treated animals (p < 0.05) compared with nontumo r and tumor-bearing control mice. Serum tumor necrosis factor alpha (T NF-alpha) levels were increased in tumor-bearing animals, but gallium nitrate had no effect on circulating levels (not detectable in nontumo r control mice versus 82 +/- 21 pg/ml in tumor-bearing mice and 107 +/ - 12 pg/ml in gallium-treated tumor-bearing mice). Concentrations of g allium in bone were undetectable in untreated control mice (<0.00005 m u g/g bone), but markedly elevated concentrations were present in gall ium-treated mice (235 +/- 6 mu g/g bone in nontumor-bearing and 155 +/ - 18 in tumor-bearing). These results indicate that gallium nitrate de creased osteoclastic bone resorption and serum calcium levels in a nud e mouse model of HHM.