In vivo and in vitro effects of WR-2721 in experimental hypercalcemia in the rat.
The effects of WR-2721 [S-2-(3-aminopropylaminoethyl)phosphorothioic acid] in two in vivo and in vitro models of experimental hypercalcemia in the rat were examined. Chronic WR-2721 administration by osmotic minipump (250 mg/kg/24 hr) reduced serum calcium from 12.0 +/- 0.1 to 9.5 +/- 1.0 mg/dl (P less than .01) in rats receiving 1,25-(OH)2 Vitamin D3. Control rats receiving Vitamin D without WR-2721 had a rise in serum calcium to 13.4 +/- 0.2 mg/dl over the same 5-day period. In an experimental form of humoral hypercalcemia of malignancy, the Walker carcinosarcoma tumor-implanted rat, WR-2721 reduced serum calcium from 13.6 +/- 0.3 to 8.4 +/- 0.6 mg/dl by 5 to 6 days (P less than .001). In vitro bone resorption assays utilizing fetal rat long bones in organ culture showed complementary results. WR-2721 (10(-4) M) blocked bone resorption (assayed as percentage of 45Ca release) induced by both conditioned medium derived from cell lines of Walker carcinosarcoma (7.6 +/- 1.4 vs. 24.0 +/- 1.8%, P less than .01) and by addition of 1,25-(OH)2 Vitamin D3 (10(-8) M) (9.8 +/- 0.8 vs. 17.3 +/- 1.0%, P less than .01). These results suggest that WR-2721 may be effective in controlling clinical hypercalcemia due to excess bone resorption.
D004999:Amifostine / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001862:Bone Resorption / Q000187:drug effects; D002117:Calcitriol / Q000633:toxicity; D002279:Carcinoma 256, Walker / Q000503:physiopathology; D005260:Female; D005978:Glutathione / Q000032:analysis; D006934:Hypercalcemia / Q000188:drug therapy*; D066298:In Vitro Techniques; D008297:Male; D009946:Organothiophosphorus Compounds / Q000494:pharmacology*; D012516:Osteosarcoma / Q000503:physiopathology; D010281:Parathyroid Hormone / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D009946:Organothiophosphorus Compounds; D010281:Parathyroid Hormone; D002117:Calcitriol; D005978:Glutathione; D004999:Amifostine