The effect of low calcium diet, mithramycin, and dichlorodimethylene bisphosphonate on humoral hypercalcemia of malignancy in nude mice transplanted with the canine adenocarcinoma tumor line (CAC-8).
The effect of a low calcium diet, mithramycin, or dichlorodimethylene bisphosphonate were evaluated in nude mice with humoral hypercalcemia of malignancy associated with the transplanted canine adenocarcinoma (CAC-8). Low calcium (0.01%) diet significantly reduced serum calcium levels in hypercalcemic nude mice and reduced urine calcium excretion to control levels. Mithramycin (8 mg/kg) decreased serum calcium concentration and urine calcium excretion to the range of control non-tumor-bearing nude mice at day 5 after a single injection, but there was no change in the number of tartrate-resistant acid phosphatase-positive osteoclasts in lumbar vertebrae. Osteoclasts from CAC 8-bearing nude mice after mithramycin administration were decreased in size, had small ruffled borders, and increased relative size of clear zones. Dichlorodimethylene bisphosphonate (Cl2MDP) (45 mg/kg) partially reduced serum calcium concentration of hypercalcemic tumor-bearing nude mice, decreased urine calcium excretion to control levels, and markedly reduced the numbers of tartrate-resistant acid phosphatase-positive osteoclasts in lumbar vertebrae. Osteoclasts from Cl2MDP-treated nude mice were smaller and had a reduced frequency of ruffled borders than saline-treated hypercalcemic nude mice. In vitro bone resorption induced by CAC-8 extract was significantly reduced by Cl2MDP and mithramycin. The results of these investigations suggest that the hypercalcemia and hypercalciuria associated with HHM in nude mice with CAC-8 are the combined result of altered calcium homeostasis in the bone, kidney, and intestine. Chemotherapeutic agents that specifically affect only bone or feeding a low calcium diet alone may not completely ameliorate the hypercalcemia of HHM.
Rosol
T J
TJ
Department of Veterinary Pathobiology, Ohio State University, Columbus.
Capen
C C
CC
D000230:Adenocarcinoma / Q000150:complications* / Q000378:metabolism; D000818:Animals; D001862:Bone Resorption / Q000187:drug effects*; D002118:Calcium / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D002460:Cell Line; D002478:Cells, Cultured; D004164:Diphosphonates / Q000627:therapeutic use*; D004285:Dogs; D005260:Female; D006934:Hypercalcemia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D010281:Parathyroid Hormone / Q000494:pharmacology; D008926:Plicamycin / Q000627:therapeutic use*
D004164:Diphosphonates; D010281:Parathyroid Hormone; D008926:Plicamycin; D002118:Calcium