Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1985 Apr;75(4):1191–1197. doi: 10.1172/JCI111815

Bone and parathyroid inhibitory effects of S-2(3-aminopropylamino)ethylphosphorothioic acid. Studies in experimental animals and cultured bone cells.

M F Attie, M D Fallon, B Spar, J S Wolf, E Slatopolsky, S Goldfarb
PMCID: PMC425444  PMID: 2985652

Abstract

S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR 2721) is a radio- and chemoprotective agent which produces hypocalcemia in humans. Intravenous injection of 30 mg/kg WR 2721 in rats and 15 mg/kg in dogs lowers serum calcium by 19 and 25%, respectively. Hypocalcemia in dogs is associated with a fall in serum immunoreactive parathyroid hormone (PTH), which suggests that the mechanism of its hypocalcemic effect is acute hypoparathyroidism. Despite this effect on PTH, in eight chronically parathyroidectomized rats on a low phosphate diet, WR 2721 reduced serum calcium from 9.4 +/- 0.6 to 7.7 +/- 0.5 mg/dl (P less than 0.01) at 3 h. Furthermore, in dogs rendered hypercalcemic by continuous infusion of PTH, WR 2721 reduced serum calcium from 11.0 +/- 0.5 to 10.6 +/- 0.5 mg/dl (P less than 0.01). To determine whether WR 2721 causes hypocalcemia by enhancing the exit of calcium from the circulation or inhibiting its entry, the drug was infused 3 h after administration of 45Ca to rats. WR 2721 did not significantly increase the rate of disappearance of 45Ca from the circulation even though serum calcium fell by 19%. However, serum 45Ca specific activity was higher at 1.5 h (P less than 0.01) and 3 h (P less than 0.05) in rats given WR 2721 than in rats given vehicle alone, which suggests that WR 2721 blocks the entry of nonradioactive calcium into the circulation, presumably from bone. In incubations with fetal rat long bone labeled in utero with 45Ca, 10(-3) M WR 2721 inhibited PTH-stimulated, but not base-line release of 45Ca. Bone resorption by primary culture of chick osteoclasts was inhibited by WR 2721 at concentrations as low as 10(-4) M in the absence of hormonal stimulation. These studies suggest that WR 2721 lowers serum calcium predominantly by blocking calcium release from bone. This acute hypocalcemic effect is at least in part independent of its effect on the parathyroid glands, and is most likely a direct effect of the agent on bone resorption.

Full text

PDF
1191

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Chambers T. J., Magnus C. J. Calcitonin alters behaviour of isolated osteoclasts. J Pathol. 1982 Jan;136(1):27–39. doi: 10.1002/path.1711360104. [DOI] [PubMed] [Google Scholar]
  2. Fleisch H., Russell R. G., Francis M. D. Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo. Science. 1969 Sep 19;165(3899):1262–1264. doi: 10.1126/science.165.3899.1262. [DOI] [PubMed] [Google Scholar]
  3. Glover D., Riley L., Carmichael K., Spar B., Glick J., Kligerman M. M., Agus Z. S., Slatopolsky E., Attie M., Goldfarb S. Hypocalcemia and inhibition of parathyroid hormone secretion after administration of WR-2721 (a radioprotective and chemoprotective agent). N Engl J Med. 1983 Nov 10;309(19):1137–1141. doi: 10.1056/NEJM198311103091901. [DOI] [PubMed] [Google Scholar]
  4. Goldfarb S., Bosanac M., Goldberg M., Agus Z. S. Effects of calcium on renal tubular phosphate reabsorption. Am J Physiol. 1978 Jan;234(1):F22–F28. doi: 10.1152/ajprenal.1978.234.1.F22. [DOI] [PubMed] [Google Scholar]
  5. Göthlin G., Ericsson J. L. The osteoclast: review of ultrastructure, origin, and structure-function relationship. Clin Orthop Relat Res. 1976 Oct;(120):201–231. [PubMed] [Google Scholar]
  6. Heath D. A., Palmer J. S., Aurbach G. D. The hypocalcemic action of colchicine. Endocrinology. 1972 Jun;90(6):1589–1593. doi: 10.1210/endo-90-6-1589. [DOI] [PubMed] [Google Scholar]
  7. Hruska K. A., Kopelman R., Rutherford W. E., Klahr S., Slatopolsky E., Greenwalt A., Bascom T., Markham J. Metabolism in immunoreactive parathyroid hormone in the dog. The role of the kidney and the effects of chronic renal disease. J Clin Invest. 1975 Jul;56(1):39–48. doi: 10.1172/JCI108077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Johnston C. C., Jr, Deiss W. P., Jr An inhibitory effect of thyrocalcitonin on calcium release in vivo and on bone metabolism in vitro. Endocrinology. 1966 Jun;78(6):1139–1143. doi: 10.1210/endo-78-6-1139. [DOI] [PubMed] [Google Scholar]
  9. Johnston C. C., Jr, Grinnan E. L., Wilson H. C., Boder G. B. Protamine-induced hypocalcemia. Endocrinology. 1970 Dec;87(6):1211–1217. doi: 10.1210/endo-87-6-1211. [DOI] [PubMed] [Google Scholar]
  10. Kiang D. T., Loken M. K., Kennedy B. J. Mechanism of the hypocalcemic effect of mithramycin. J Clin Endocrinol Metab. 1979 Feb;48(2):341–344. doi: 10.1210/jcem-48-2-341. [DOI] [PubMed] [Google Scholar]
  11. Lloyd W., Fang V. S., Wells H., Tashjian A. H., Jr 2-Thiophenecarboxylic acid: a hypoglycemic, antilipolytic agent with hypocalcemic and hypophosphatemic effects in rats. Endocrinology. 1969 Oct;85(4):763–768. doi: 10.1210/endo-85-4-763. [DOI] [PubMed] [Google Scholar]
  12. O'Riordan J. L., Aurbach G. D. Mode of action of thyrocalcitonin. Endocrinology. 1968 Feb;82(2):377–383. doi: 10.1210/endo-82-2-377. [DOI] [PubMed] [Google Scholar]
  13. Osdoby P., Martini M. C., Caplan A. I. Isolated osteoclasts and their presumed progenitor cells, the monocyte, in culture. J Exp Zool. 1982 Dec 30;224(3):331–344. doi: 10.1002/jez.1402240306. [DOI] [PubMed] [Google Scholar]
  14. Phillips T. L., Kane L., Utley J. F. Radioprotection of tumor and normal tissues by thiophosphate compounds. Cancer. 1973 Sep;32(3):528–535. doi: 10.1002/1097-0142(197309)32:3<528::aid-cncr2820320303>3.0.co;2-c. [DOI] [PubMed] [Google Scholar]
  15. Purdie J. W., Inhaber E. R., Schneider H., Labelle J. L. Interaction of cultured mammalian cells with WR-2721 and its thiol, WR-1065: implications for mechanisms of radioprotection. Int J Radiat Biol Relat Stud Phys Chem Med. 1983 May;43(5):517–527. doi: 10.1080/09553008314550611. [DOI] [PubMed] [Google Scholar]
  16. RAISZ L. G. BONE RESORPTION IN TISSUE CULTURE. FACTORS INFLUENCING THE RESPONSE TO PARATHYROID HORMONE. J Clin Invest. 1965 Jan;44:103–116. doi: 10.1172/JCI105117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Rosenbaum R. W., Hruska K. A., Korkor A., Anderson C., Slatopolsky E. Decreased phosphate reabsorption after renal transplantation: Evidence for a mechanism independent of calcium and parathyroid hormone. Kidney Int. 1981 Apr;19(4):568–578. doi: 10.1038/ki.1981.54. [DOI] [PubMed] [Google Scholar]
  18. Tabachnik N. F., Peterson C. M., Cerami A. Studies on the reduction of sputum viscosity in cystic fibrosis using an orally absorbed protected thiol. J Pharmacol Exp Ther. 1980 Aug;214(2):246–249. [PubMed] [Google Scholar]
  19. Talmage R. V., Anderson J. J., Cooper C. W. The influence of calcitonins on the disappearance of radiocalcium and radiophosphorus from plasma. Endocrinology. 1972 May;90(5):1185–1191. doi: 10.1210/endo-90-5-1185. [DOI] [PubMed] [Google Scholar]
  20. Teitelbaum S. L., Stewart C. C., Kahn A. J. Rodent peritoneal macrophages as bone resorbing cells. Calcif Tissue Int. 1979 Jul 3;27(3):255–261. doi: 10.1007/BF02441194. [DOI] [PubMed] [Google Scholar]
  21. Yuhas J. M., Spellman J. M., Culo F. The role of WR-2721 in radiotherapy and/or chemotherapy. Cancer Clin Trials. 1980 Fall;3(3):211–216. [PubMed] [Google Scholar]
  22. Yuhas J. M., Storer J. B. Differential chemoprotection of normal and malignant tissues. J Natl Cancer Inst. 1969 Feb;42(2):331–335. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES