Prolonged decrease of serum calcium concentration by murine gamma-interferon in hypercalcemic, human tumor (EC-GI)-bearing nude mice.
Murine gamma-interferon (MuIFN-gamma) is a potent inhibitor of bone resorption induced by interleukin 1 and parathyroid hormone-related protein in vitro. To investigate whether MuIFN-gamma is also effective in vivo, the cytokine was injected s.c. into hypercalcemic, tumor (EC-GI)-bearing nude mice, in which parathyroid hormone-related protein and interleukin 1 alpha are synergistically responsible for causing humoral hypercalcemia. When MuIFN-gamma was injected s.c. at a dose of 1 to 20 x 10(4) units for 5 days consecutively, serum calcium concentrations in the tumor-bearing mice decreased in a dose-dependent manner. The minimal effective dose was 5 x 10(4) units/mouse. Unlike calcitonin, which decreased the serum calcium concentration for only 1 to 2 days despite continuous daily injections, MuIFN-gamma decreased it for more than 7 days even after the injections had been stopped. Human gamma-interferon was completely ineffective. The decrease in serum calcium concentration was accompanied by a decrease in urinary calcium excretion. Histological examination of the femur revealed a decreased number of osteoclasts in the MuIFN-gamma-treated mice. Furthermore, MuIFN-gamma, when injected into nude mice or normal mice at a dose of 15 x 10(4) units for 3 days, almost completely abolished the formation of multinucleated osteoclast-like cells in vitro. These findings suggest that MuIFN-gamma suppresses the formation and maturation of osteoclasts and inhibits osteoclastic bone resorption, resulting in the prolonged decrease of serum calcium concentration seen in hypercalcemic, tumor-bearing nude mice. Therefore, bone resorption inhibitors like MuIFN-gamma, which ameliorate humoral hypercalcemia without an escape phenomenon, are potentially useful for the treatment of malignancy-associated hypercalcemia.
Sato
K
K
Department of Medicine, Tokyo Women's Medical College, Japan.
Satoh
T
T
Shizume
K
K
Yamakawa
Y
Y
Ono
Y
Y
Demura
H
H
Akatsu
T
T
Takahashi
N
N
Suda
T
T
D000818:Animals; D001862:Bone Resorption; D002116:Calcitonin / Q000494:pharmacology; D002118:Calcium / Q000652:urine; D006801:Humans; D006934:Hypercalcemia / Q000628:therapy*; D007371:Interferon-gamma / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000150:complications / Q000628:therapy*; D044162:Parathyroid Hormone-Related Protein; D010710:Phosphates / Q000652:urine; D011506:Proteins / Q000502:physiology; D011994:Recombinant Proteins; D013045:Species Specificity
D007375:Interleukin-1; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D010710:Phosphates; D011506:Proteins; D011994:Recombinant Proteins; D007371:Interferon-gamma; D002116:Calcitonin; D002118:Calcium