The inhibitory effect of murine
interferon gamma (muIFN gamma) on humoral
hypercalcemia in nude mice bearing lower-
jaw cancer (LJC-1-JCK), in which
parathyroid-hormone(PTH)-related
protein is responsible for causing humoral
hypercalcemia by activating
bone resorption, was examined in comparison with that of a new
bisphosphonate, 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (
alendronate). muIFN gamma was injected into
tumor-bearing nude mice for 5 days before the establishment of
hypercalcemia. The increase of plasma
calcium concentration was delayed and this effect continued for more than 6 days even after the injection was stopped.
Alendronate markedly suppressed
hypercalcemia in
tumor-bearing nude mice but this inhibitory effect continued for less than 6 days. Neither muIFN gamma nor
alendronate affected the
tumor volume or serum PTH-related
protein concentration. Injection of muIFN gamma into mice for 3 days almost completely abolished the formation of multinucleated osteoclast-like cells from bone marrow cells in vitro, whereas injection of
alendronate into mice had no effect. These findings suggested that muIFN gamma suppressed the formation of osteoclasts, resulting in the prolonged decrease of plasma
calcium concentration in hypercalcemic
tumor-bearing nude mice, whereas
alendronate is cytotoxic to functionally mature osteoclasts and inhibited osteoclastic
bone resorption, resulting in a marked decrease in the plasma
calcium concentration in
tumor-bearing hypercalcemic nude mice.