Reversal of hypercalcemia with the vitamin D analogue EB1089 in a human model of squamous cancer.
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 > or =0.5 cm3. When total calcium was 22.85 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.
Department of Medicine, McGill University and Royal Victoria Hospital, Montreal, Quebec, Canada.
K
K
El Abdaimi
V
V
Papavasiliou
S A
SA
Rabbani
J S
JS
Rhim
D
D
Goltzman
R
R
Kremer
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000150:complications* / Q000473:pathology / Q000821:virology; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed / Q000637:transplantation; D002472:Cell Transformation, Viral; D004354:Drug Screening Assays, Antitumor; D011905:Genes, ras; D006801:Humans; D006934:Hypercalcemia / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D027383:Papillomaviridae / Q000472:pathogenicity; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000378:metabolism*; D012878:Skin Neoplasms / Q000150:complications* / Q000473:pathology / Q000821:virology
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; C111392:parathyroid hormone-related protein (7-34)amide, Asn(10), Leu(11)-; D002117:Calcitriol; C078903:seocalcitol