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. 1988 Nov;82(5):1798–1802. doi: 10.1172/JCI113794

Antibodies to parathyroid hormone-related protein lower serum calcium in athymic mouse models of malignancy-associated hypercalcemia due to human tumors.

S C Kukreja 1, D H Shevrin 1, S A Wimbiscus 1, P R Ebeling 1, J A Danks 1, C P Rodda 1, W I Wood 1, T J Martin 1
PMCID: PMC442751  PMID: 2846659

Abstract

A parathyroid hormone-related protein (PTHrP) has recently been isolated from tumors associated with hypercalcemia. In the present study, we tested the effects of neutralizing antisera to the PTHrP on serum calcium and urine cAMP in two animal models of malignancy-associated hypercalcemia. The animal models consisted of (a) a human squamous cell lung cancer and (b) a human laryngeal cancer, both serially carried in athymic mice. The antisera specifically reduced the elevated serum calcium and urinary cAMP levels in the tumor-bearing animals. We conclude that PTHrP plays a major role in the pathogenesis of malignancy-associated hypercalcemia.

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Selected References

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  1. Abramson E. C., Kukla L. J., Shevrin D. H., Lad T. E., McGuire W. P., Kukreja S. C. A model for malignancy-associated humoral hypercalcemia. Calcif Tissue Int. 1984 Sep;36(5):563–567. doi: 10.1007/BF02405367. [DOI] [PubMed] [Google Scholar]
  2. Bertolini D. R., Nedwin G. E., Bringman T. S., Smith D. D., Mundy G. R. Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors. Nature. 1986 Feb 6;319(6053):516–518. doi: 10.1038/319516a0. [DOI] [PubMed] [Google Scholar]
  3. Burtis W. J., Wu T., Bunch C., Wysolmerski J. J., Insogna K. L., Weir E. C., Broadus A. E., Stewart A. F. Identification of a novel 17,000-dalton parathyroid hormone-like adenylate cyclase-stimulating protein from a tumor associated with humoral hypercalcemia of malignancy. J Biol Chem. 1987 May 25;262(15):7151–7156. [PubMed] [Google Scholar]
  4. Gowen M., Mundy G. R. Actions of recombinant interleukin 1, interleukin 2, and interferon-gamma on bone resorption in vitro. J Immunol. 1986 Apr 1;136(7):2478–2482. [PubMed] [Google Scholar]
  5. Horiuchi N., Caulfield M. P., Fisher J. E., Goldman M. E., McKee R. L., Reagan J. E., Levy J. J., Nutt R. F., Rodan S. B., Schofield T. L. Similarity of synthetic peptide from human tumor to parathyroid hormone in vivo and in vitro. Science. 1987 Dec 11;238(4833):1566–1568. doi: 10.1126/science.3685994. [DOI] [PubMed] [Google Scholar]
  6. Ibbotson K. J., Harrod J., Gowen M., D'Souza S., Smith D. D., Winkler M. E., Derynck R., Mundy G. R. Human recombinant transforming growth factor alpha stimulates bone resorption and inhibits formation in vitro. Proc Natl Acad Sci U S A. 1986 Apr;83(7):2228–2232. doi: 10.1073/pnas.83.7.2228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Kemp B. E., Moseley J. M., Rodda C. P., Ebeling P. R., Wettenhall R. E., Stapleton D., Diefenbach-Jagger H., Ure F., Michelangeli V. P., Simmons H. A. Parathyroid hormone-related protein of malignancy: active synthetic fragments. Science. 1987 Dec 11;238(4833):1568–1570. doi: 10.1126/science.3685995. [DOI] [PubMed] [Google Scholar]
  8. Kukreja S. C., Rosol T. J., Shevrin D. H., York P. A. Quantitative bone histomorphometry in nude mice bearing a human squamous cell lung cancer. J Bone Miner Res. 1988 Jun;3(3):341–346. doi: 10.1002/jbmr.5650030314. [DOI] [PubMed] [Google Scholar]
  9. Kukreja S. C., Shemerdiak W. P., Lad T. E., Johnson P. A. Elevated nephrogenous cyclic AMP with normal serum parathyroid hormone levels in patients with lung cancer. J Clin Endocrinol Metab. 1980 Jul;51(1):167–169. doi: 10.1210/jcem-51-1-167. [DOI] [PubMed] [Google Scholar]
  10. Mangin M., Webb A. C., Dreyer B. E., Posillico J. T., Ikeda K., Weir E. C., Stewart A. F., Bander N. H., Milstone L., Barton D. E. Identification of a cDNA encoding a parathyroid hormone-like peptide from a human tumor associated with humoral hypercalcemia of malignancy. Proc Natl Acad Sci U S A. 1988 Jan;85(2):597–601. doi: 10.1073/pnas.85.2.597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Martin T. J., Ng K. W., Partridge N. C., Livesey S. A. Hormonal influences on bone cells. Methods Enzymol. 1987;145:324–336. doi: 10.1016/0076-6879(87)45019-2. [DOI] [PubMed] [Google Scholar]
  12. McGuire J. L., Marks S. C., Jr The effects of parathyroid hormone on bone cell structure and function. Clin Orthop Relat Res. 1974 May;(100):392–405. [PubMed] [Google Scholar]
  13. Moseley J. M., Kubota M., Diefenbach-Jagger H., Wettenhall R. E., Kemp B. E., Suva L. J., Rodda C. P., Ebeling P. R., Hudson P. J., Zajac J. D. Parathyroid hormone-related protein purified from a human lung cancer cell line. Proc Natl Acad Sci U S A. 1987 Jul;84(14):5048–5052. doi: 10.1073/pnas.84.14.5048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Mundy G. R., Ibbotson K. J., D'Souza S. M., Simpson E. L., Jacobs J. W., Martin T. J. The hypercalcemia of cancer. Clinical implications and pathogenic mechanisms. N Engl J Med. 1984 Jun 28;310(26):1718–1727. doi: 10.1056/NEJM198406283102607. [DOI] [PubMed] [Google Scholar]
  15. Mundy G. R., Ibbotson K. J., D'Souza S. M. Tumor products and the hypercalcemia of malignancy. J Clin Invest. 1985 Aug;76(2):391–394. doi: 10.1172/JCI111984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Raisz L. G., Simmons H. A., Sandberg A. L., Canalis E. Direct stimulation of bone resorption by epidermal growth factor. Endocrinology. 1980 Jul;107(1):270–273. doi: 10.1210/endo-107-1-270. [DOI] [PubMed] [Google Scholar]
  17. Rodan S. B., Noda M., Wesolowski G., Rosenblatt M., Rodan G. A. Comparison of postreceptor effects of 1-34 human hypercalcemia factor and 1-34 human parathyroid hormone in rat osteosarcoma cells. J Clin Invest. 1988 Mar;81(3):924–927. doi: 10.1172/JCI113404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Rude R. K., Sharp C. F., Jr, Fredericks R. S., Oldham S. B., Elbaum N., Link J., Irwin L., Singer F. R. Urinary and nephrogenous adenosine 3',5'-monophosphate in the hypercalcemia of malignancy. J Clin Endocrinol Metab. 1981 Apr;52(4):765–771. doi: 10.1210/jcem-52-4-765. [DOI] [PubMed] [Google Scholar]
  19. Shevrin D. H., Lad T. E., Kukreja S. C. Effect of epidermal growth factor infusion on serum and urine calcium in mice. J Bone Miner Res. 1987 Aug;2(4):297–301. doi: 10.1002/jbmr.5650020406. [DOI] [PubMed] [Google Scholar]
  20. Sternberger L. A., Hardy P. H., Jr, Cuculis J. J., Meyer H. G. The unlabeled antibody enzyme method of immunohistochemistry: preparation and properties of soluble antigen-antibody complex (horseradish peroxidase-antihorseradish peroxidase) and its use in identification of spirochetes. J Histochem Cytochem. 1970 May;18(5):315–333. doi: 10.1177/18.5.315. [DOI] [PubMed] [Google Scholar]
  21. Stewart A. F., Horst R., Deftos L. J., Cadman E. C., Lang R., Broadus A. E. Biochemical evaluation of patients with cancer-associated hypercalcemia: evidence for humoral and nonhumoral groups. N Engl J Med. 1980 Dec 11;303(24):1377–1383. doi: 10.1056/NEJM198012113032401. [DOI] [PubMed] [Google Scholar]
  22. Stewart A. F., Mangin M., Wu T., Goumas D., Insogna K. L., Burtis W. J., Broadus A. E. Synthetic human parathyroid hormone-like protein stimulates bone resorption and causes hypercalcemia in rats. J Clin Invest. 1988 Feb;81(2):596–600. doi: 10.1172/JCI113358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Stewart A. F., Vignery A., Silverglate A., Ravin N. D., LiVolsi V., Broadus A. E., Baron R. Quantitative bone histomorphometry in humoral hypercalcemia of malignancy: uncoupling of bone cell activity. J Clin Endocrinol Metab. 1982 Aug;55(2):219–227. doi: 10.1210/jcem-55-2-219. [DOI] [PubMed] [Google Scholar]
  24. Stewart A. F., Wu T., Goumas D., Burtis W. J., Broadus A. E. N-terminal amino acid sequence of two novel tumor-derived adenylate cyclase-stimulating proteins: identification of parathyroid hormone-like and parathyroid hormone-unlike domains. Biochem Biophys Res Commun. 1987 Jul 31;146(2):672–678. doi: 10.1016/0006-291x(87)90581-x. [DOI] [PubMed] [Google Scholar]
  25. Strewler G. J., Stern P. H., Jacobs J. W., Eveloff J., Klein R. F., Leung S. C., Rosenblatt M., Nissenson R. A. Parathyroid hormonelike protein from human renal carcinoma cells. Structural and functional homology with parathyroid hormone. J Clin Invest. 1987 Dec;80(6):1803–1807. doi: 10.1172/JCI113275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Suva L. J., Winslow G. A., Wettenhall R. E., Hammonds R. G., Moseley J. M., Diefenbach-Jagger H., Rodda C. P., Kemp B. E., Rodriguez H., Chen E. Y. A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression. Science. 1987 Aug 21;237(4817):893–896. doi: 10.1126/science.3616618. [DOI] [PubMed] [Google Scholar]
  27. Szabo M., Kovathana N., Gordon K., Frohman L. A. Effect of passive immunization with an antiserum to thyrotropin (TSH)-releasing hormone on plasma TSH levels in thyroidectomized rats. Endocrinology. 1978 Mar;102(3):799–805. doi: 10.1210/endo-102-3-799. [DOI] [PubMed] [Google Scholar]
  28. Tashjian A. H., Jr, Voelkel E. F., Lloyd W., Derynck R., Winkler M. E., Levine L. Actions of growth factors on plasma calcium. Epidermal growth factor and human transforming growth factor-alpha cause elevation of plasma calcium in mice. J Clin Invest. 1986 Nov;78(5):1405–1409. doi: 10.1172/JCI112728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Yates A. J., Gutierrez G. E., Smolens P., Travis P. S., Katz M. S., Aufdemorte T. B., Boyce B. F., Hymer T. K., Poser J. W., Mundy G. R. Effects of a synthetic peptide of a parathyroid hormone-related protein on calcium homeostasis, renal tubular calcium reabsorption, and bone metabolism in vivo and in vitro in rodents. J Clin Invest. 1988 Mar;81(3):932–938. doi: 10.1172/JCI113406. [DOI] [PMC free article] [PubMed] [Google Scholar]

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