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Reversal of Hypercalcemia with the Vitamin D Analogue EB1089 in a Human Model of Squamous Cancer¹

Departments of Medicine, McGill University and Royal Victoria Hospital, Montreal, Quebec H3A 1A1, Canada [K. E. A., S. A. R., D. G., R. K.], and Laboratory of Molecular Oncology, National Cancer Institute, Frederick, Maryland 21702 [J. S. R.]

EB1089, an analogue of 1,25 dihydroxyvitamin D with low calcemic activity is a potent inhibitor of parathyroid hormone-related peptide (PTHRP) production in vitro. The purpose of the present study was to determine whether EB1089 could reverse established hypercalcemia in BALB C nude mice implanted s.c. with a human epithelial cancer previously shown to produce high levels of PTHRP in vitro. Total plasma calcium was monitored before and after tumor development and increased steadily when the tumor reached 0.5 cm³. When total calcium was 2.85 mmol/liter, animals were treated with a constant infusion of EB1089 or vehicle alone for a period of 2 weeks. A significant and sustained reduction of plasma calcium from 3.2 ± 0.1 to 2.7 ± 0.08 (P < 0.01) mmol/liter was observed during infusion with EB1089. In contrast, calcium levels in vehicle-treated animals continued to rise during the infusion period. Tumor growth velocity also slowed significantly after the administration of EB1089 as compared with vehicle-treated animals. Plasma PTHRP levels measured at the end of the 2 weeks’ infusion period were significantly lower in animals treated with EB1089 as compared with animals treated with vehicle alone (44 ± 8 pg/ml versus 194 ± 35 pg/ml, P < 0.001). These results, therefore, demonstrate that EB1089 can reverse established hypercalcemia in a human model of squamous cancer.

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