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The Walker 256/B carcinosarcoma in thyroparathyroidectomized rats: A model to evaluate inhibitors of bone resorption

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Summary

The Walker 256/B mammary carcino-sarcoma implanted in male Fischer rats was used to evaluate bone resorption inhibitors. The model was improved by thyroparathyroidectomizing the animals to avoid counter-regulation by parathyroid hormone or calcitonin, by pair-feeding them, and by using 2 hour fasting calciuria as a resorption index to minimize the influence of differences in growth or in intestinal calcium absorption. Over a 10 day period, the control animals displayed a progressive increase of plasma calcium (Ca) and fasting urinary Ca excretion, a decrease of plasma phosphate, and an increase of urinary phosphate excretion. Osteocalcin did not change. The daily administration of dichloromethylene bisphosphonate (Cl2MBP) totally prevented the increase of fasting urinary Ca excretion, whereas plasma Ca remained at a higher level than thyroparathyroidectomized (TPTX) control rats. Osteocalcin decreased. Two new aminobisphosphonates, 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (AHBuBP), and 6-amino-1-hydroxyhexylidene-1,1-bisphosphonate (AHHexBP) had a similar effect. The order of potency shown by the three bisphosphonates was similar to that reported using the metaphyseal bone density evaluation method in growing rats: AHBuBP>AHHexBP>Cl2MBP, the difference each time being one order of magnitude. The analysis of the relationship between urinary and plasma values in tumor-bearing animals suggested an increased renal tubular reabsorption of Ca and a decreased reabsorption of phosphate (Pi). Therefore, in this model of malignant osteolysis, urinary Ca excretion is the best marker for bone resorption.

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References

  1. Mundy GR, Martin TJ (1982) The hypercalcemia of malignancy: pathogenesis and management. Metabolism 31: 1247–1277

    Article  PubMed  CAS  Google Scholar 

  2. Mundy GR, Ibbotson KJ, D'Souza SM, Simpson EL, Jacobs JW, Martin TJ (1984) The hypercalcemia of cancer. Clinical implications and pathogenic mechanisms. N Engl J Med 310:1718–1727

    Article  PubMed  CAS  Google Scholar 

  3. Martodam RR, Thornton KS, Sica D, D'Souza SM, Flora L, Mundy GR (1983) The effects of dichloromethylene diphosphonate on hypercalcemia and other parameters of the humoral hypercalcemia of malignancy in the rat Leydig cell tumor. Calcif Tissue Int 35:512–519

    Article  PubMed  CAS  Google Scholar 

  4. Johnson KY, Wesseler MA, Olson HM, Martodam RR, Poser JW (1982) The effects of diphosphonates on tumor-induced hypercalcemia and osteolysis in Walker carcinosarcoma 256 (W-256) of rats. In: Donath A, Courvoisier B (eds) Diphosphonates and bone. Symposium CEMO IV, Nyon, Switzerland, Eds Médecine et Hygiène, Genève, pp 386–389

    Google Scholar 

  5. Jung A, Bornand J, Mermillod B, Edouard C, Meunier PJ (1984) Inhibition by bisphosphonates of bone resorption induced by the Walker tumor of the rat. Cancer Res 44:3007–3011

    PubMed  CAS  Google Scholar 

  6. Guaitani A, Polentarutti N, Filippeschi S, Marmonti L, Corti F, Italia C, Coccioli MG, Mantovani A, Garattini S (1984) Effects of disodium etidronate in murine tumor models. Eur J Clin Oncol 20:685–693

    Article  CAS  Google Scholar 

  7. Ralston SH, Fogelman I, Gardner MD, Dryburgh FJ, Cowan RA, Boyle IT (1984) Hypercalcemia of malignancy: evidence for a non-parathyroid humoral agent with an effect on renal tubular handling of calcium. Clin Sci 66:187–191

    PubMed  CAS  Google Scholar 

  8. Rizzoli R, Caverzasio J, Fleisch H, Bonjour JP (1986) Parathyroid hormone-like changes of renal calcium and phosphate reabsorption induced by Leydig cell tumor in thyroparathyroidectomized rats. Endocrinology 119:1004–1009

    PubMed  CAS  Google Scholar 

  9. Nordin BEC, Horsman A, Aaron J (1976) Diagnostic procedures. In: Nordin BEC (ed) Calcium, phosphate and magnesium metabolism. Churchill Livingstone, Edinburgh, London, New York, pp 471–472

    Google Scholar 

  10. Minne H, Raue F, Bellwinkel S, Ziegler R (1975) The hypercalcemic syndrome in rats bearing the Walker carcinosarcoma 256. Acta Endocrinol 76:613–624

    Google Scholar 

  11. Schmid-Gayk H, Löhrke H, Fischkal A, Goerttler K, Hofmann F (1979) Urinary cyclic AMP and bone histology in Walker carcinosarcoma: evidence of parathyroid hormone-like activity. Eur J Cancer 15:1211–1218

    Google Scholar 

  12. Fleisch H (1983) Bisphosphonates: mechanisms of action and clinical applications. In: Peck WA (ed) Bone and Mineral Research, annual 1. Excerpta Medica, Amsterdam, Oxford, Princeton pp 319–357

    Google Scholar 

  13. Schenk R, Eggli P, Felix R, Fleisch H, Rosini S (1986) Quantitative morphometric evaluation of the inhibitory activity of new aminobisphosphonates on bone resorption in the rat. Calcif Tissue Int 38:342–349

    PubMed  CAS  Google Scholar 

  14. Chen PS, Toribara TY, Warner H (1956) Microdetermination of phosphorus. Anal Chem 28:1756–1758

    Article  CAS  Google Scholar 

  15. Nishimoto SK, Price PA (1980) Secretion of the vitamin K-dependent protein of bone by rat osteosarcoma cells. Evidence for an intracellular precursor. J Biol Chem 255:6579–6583

    PubMed  CAS  Google Scholar 

  16. Brown BL, Albano JDM, Ekins RP, Sgherzi AM (1971) A simple and sensitive saturation assay method for the measurement of adenosine 3′,5′-cyclic monophosphate. Biochem J 121:561–562

    PubMed  CAS  Google Scholar 

  17. Seyberth HW, Bonsch G, Müller H, Minne HW, Erlenmaier T, Strein K, Imbeck H, Mrongovius R (1980) Prostaglandin E production and hypercalcemia in rats bearing the Walker carcinosarcoma. Br J Cancer 42:455–461

    PubMed  CAS  Google Scholar 

  18. Brown JP, Delmas PD, Malaval L, Edouard C, Chapuy MC, Meunier PJ (1984) Serum bone Gla protein: a specific marker for bone formation in postmenopausal osteoporosis. Lancet i:1091–1093

    Article  Google Scholar 

  19. Tam CS, Heersche JNM, Santora A, Spiegel AM (1984) Skeletal response in rats following the implantation of hypercalcemia-producing Leydig cell tumors. Metabolism 33:50–53

    Article  PubMed  CAS  Google Scholar 

  20. Insogna KL, Stewart AF, Vignery AMC, Weir EC, Namnum PA, Baron RE, Kirkwood JM, Deftos LM, Broadus AE (1984) Biochemical and histomorphometric characterization of a rat model for humoral hypercalcemia of malignancy. Endocrinology 114:888–896

    Article  PubMed  CAS  Google Scholar 

  21. Stronski S, Trechsel U, Fleisch H (1986) Plasma osteocalcin: lack of relation with bone resorption and effect of bisphosphonates in rats. Calcif Tissue Int 38:539

    Google Scholar 

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Authors and Affiliations

  1. Department of Pathophysiology, University of Berne, Murtenstrasse 35, CH-3010, Berne, Switzerland

    R. Rizzoli & H. Fleisch

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  1. R. Rizzoli
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  2. H. Fleisch
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Rizzoli, R., Fleisch, H. The Walker 256/B carcinosarcoma in thyroparathyroidectomized rats: A model to evaluate inhibitors of bone resorption. Calcif Tissue Int 41, 202–207 (1987). https://doi.org/10.1007/BF02555239

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  • DOI: https://doi.org/10.1007/BF02555239

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