Skip to main content
NCBI home page
Journal of Cancer Research and Clinical Oncology logoLink to Journal of Cancer Research and Clinical Oncology
. 1990 Jul;116(4):341–350. doi: 10.1007/BF01612916

Anticancer-agent-linked phosphonates with antiosteolytic and antineoplastic properties: a promising perspective in the treatment of bone-related malignancies?

T Klenner 1,✉, F Wingen 2, B K Keppler 3, B Krempien 4, D SchmÄhl 1
PMCID: PMC12201255  PMID: 2152296

Abstract

Bisphosphonates are compounds with a high affinity for bone and other calcified tissues. They inhibit tumor-induced bone destruction and the associated hypercalcemia by hindering the activity of the osteoclasts. Owing to a long biological half-life of bisphosphonates in the bone, a treatment using a prophylactic regimen seems possible. This paper summarizes preclinical studies with the bisphosphonate 3-amino-1-hydroxypropylidene-1, 1-diphosphonic acid and two methyl derivatives; S-N,N-dimethylamino-1-hydroxypropylidene-1,1-diphosphonic acid and 4-N,N-dimetyhlamino-1-hydroxybutylidene-1, 1-diphosphonic acid with respect to their bone-protecting activity in therapy as well as in prophylaxis. To find substances that are useful for the treatment of primary tumor, as well as bone metastasis, we synthesized and testedcis-diammine[nitrilotris(methylphosphonato) (2-)-O 1,N1]platinum(II) andcis-diammine{[bis-(phosphonatomethyl)amino]acetato(2-)-O1, N1} platinum(II), which contain both an osteotropic and an antineoplastic moiety. Experiments were carried out: (a) in the intratibial transplanted Walker carcinosarcoma 256B of the rat, which mimics osteolytic bone metastasis, and (b) in the transplantable osteosarcoma of the rat, which shows a histology and metastatic pattern similar to that found in man. These investigations indicate that it is possible to effect adjuvant therapy of bone metastases by combination of two compounds with different properties into one structure without losing the therapeutic characteristics of the parent compounds. They thus provide evidence that it may be possible to design compounds well suited for the therapeutic or prophylactic treatment of bone-related malignancies.

Key words: Bisphosphonates, Osteosarcoma, Bone metastasis, Prophylactic treatment, Anticancer-agent-linked phosphonates

Abbreviations

NMR

nuclear magnetic resonance

WCS

Walker carcinosarcoma 256B

APD

3-amino-1-hydroxypropylidene-1,1-diphosphonic acid

3Me2APD

theN-dimethyl derivative of APD

4Me2ABD

A-N, N-dimethylamino-1-hydroxybutylidene-1,1-diphosphonic acid

AMDP

cis-diammine[nitrilotris(methylphosphonato)(2-)-O 1,N 1]platinum(II)

DBP

cis-diammine{[bis(phosphonatomethyl)amino]acetato(2-)-O 1,N 1}platmum(II)

References

  1. Adami S, Salvagno G, Guarrera G, Montesanti F, Garavelli S, Rosini S, LoCascio V (1986) Treatment of Paget's disease of bone with intravenous 4-amino-1-hydroxybutylidene-1,1-bis-phosphonate. Calcif Tissue Int 39:226–229 [DOI] [PubMed] [Google Scholar]
  2. Attardo-Parrinello G, Merlini G, Pavesi F, Crema F, Fiorentini ML, Ascari E (1987) Effects of a new aminodiphosphonate (aminohydroxybutylidene diphosphonate) in patients with osteolytic lesions from metastases and myelomatosis. Arch Intern Med 147:1629–1633 [PubMed] [Google Scholar]
  3. Boonekamp P, van der Wee-Pals LJA, van Wijk-van Lennep MML, Wil Thesing C, Bijvoet OLM (1986) Two modes of action of bis-phosphonates on osteoclastic resorption of mineralized matrix. Bone and Mineral 1:27–39 [PubMed] [Google Scholar]
  4. Boonekamp P, Löwik LJA, van der Wee-Pals LJA, van Wijk-van Lennep MML, Bijvoet OLM (1987) Enhancement of the inhibitory action of APD on the transformation of osteoclast precursors into resorbing cells after dimethylation of the amino group. Bone and Mineral 2:29–42 [PubMed] [Google Scholar]
  5. Canfield RE (1987) Rationale for disphosphonate therapy in hypercalcemia of malignancy. Am J Med 82:1–5 [DOI] [PubMed] [Google Scholar]
  6. Coleman RE, Rubens RD (1987) 3(Amino-1,1-hydroxypropylidene) bisphosphonate (APD) for hypercalcemia of breast cancer. Br J Cancer 56:465–469 [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fogelman I (1982) Diphosphonate bone scanning agents — current concepts. Eur J Nucl Med 7:506–509 [DOI] [PubMed] [Google Scholar]
  8. Guaitani A, Polentarutti N, Fillipeschi S, Marmoti L, Corti F, Italia C, Coccioli G, Donelli MG, Mantovani A, Gerattini S (1984) Effects of disodium etidronate in murine tumor models. Eur J Cancer Clin Oncol 20:685–693 [DOI] [PubMed] [Google Scholar]
  9. Guarino AM, Miller DS, Arnold ST, Pritchard JB, Davis RD, Urbanek MA, Miller TJ, Litterst CL (1979) Platinate Toxicity: Past, present, and prospects. Cancer Treat Rep 63:1475–1483 [PubMed] [Google Scholar]
  10. Harinck HIJ, Papapoulos SE, Blanksma HJ, Moolenaar AJ, Vermeij P, Bijvoet OLM (1987) Paget's disease of bone: early and late responses to three different modes of treatment with amino-hydroxypropylidene bisphosphonate (APD). Br Med J 295:1301–1305 [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. van Holten-Verzantvoort AT, Bijvoet OLM, Hermans J, Harinck HIJ, Elte JWF, Beex LVAM, Cleton FJ, Kroon HM, Vermey P, Neijt JP, Biljham G (1987) Reduced morbidity from skeletal metastases in breast cancer patients during long-term bisphosphonate (APD) treatment. Lancet 10:983–985 [DOI] [PubMed] [Google Scholar]
  12. Johnson KF, Wesseler MA, Martodam RR, Olson HM, Poser JW (1982) The effects of diphosphonates on tumor-induced hypercalcemia and osteolysis in Walker carcinosarcoma 256 (WLSG) in rats. Proc Am Assoc Cancer Res 23:896 [Google Scholar]
  13. Jung A (1982) Comparison of two parenteral diphosphonates in hypercalcemia of malignancy. Am J Med 72:221–226 [DOI] [PubMed] [Google Scholar]
  14. Kalbfleisch JD, Prentice RE (1980) The statistical analysis of failure time data. Wiley, New York [Google Scholar]
  15. Kanis JA (ed) (1987) Clodronate — a new perspective in the treatment of neoplastic bone disease. Bone 8 [Suppl 1] [PubMed]
  16. Klenner T, Münch H, SchmÄhl D, Keppler B (1988) Efficacy of new cisplatin-linked biphosphonates in transplantable rat osteosarcoma. J Cancer Res Clin Oncol 114:S162 [Google Scholar]
  17. Klenner T, Keppler B, Amelung F, SchmÄhl D (1989) A new cisplatin-linked phosphonate superior to cisplatin in the transplantable osteosarcoma of the rat. Calcif Tiss Int [Suppl] 44:105 [Google Scholar]
  18. Koziol AJ, Donna AM (1981) A distribution-free test for tumor growth curve analysis with application to an animal tumor immunotherapy experiment. Biometrics 37:383–390 [PubMed] [Google Scholar]
  19. Krempien B, Diel B, Jöckle-Kretz B, Büchele R, Andre L (1984) The Walker carcinosarcoma 256 as an experimental model of bone metastasis. Influence of skeletal metabolism on the development of bone metastases. Verh Dtsch Ges Pathol 68:211–216 [Google Scholar]
  20. Krempien B, Wingen F, Eichmann T, Müller M, SchmÄhl D (1988) Protective effects of a prophylactic treatment with the bisphosphonate 3-amino-1-hydroxypropane-1,1-bisphosphonic acid on the development of tumor osteopathies in the rat: experimental studies with the Walker carcinosarcoma 256. Oncology 45:41–46 [DOI] [PubMed] [Google Scholar]
  21. Löwik CWGM, van der Pluijm G, Bijvoet OLM (1987) Migration and phenotypic transformation of osteoclast-precursors into mature osteoclasts: the effect of dimethyl-APD (Me2APD). Calcif Tissue Int 41 [Suppl 2]: 49 [DOI] [PubMed] [Google Scholar]
  22. Manegold C, Krempien B, Kaufmann M, Schwechheimer K, Schettler G (1988) The value of bone marrow examination for tumor staging in breast cancer. J Cancer Res Clin Oncol 114:425–428 [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Marie PJ, Hott M, Garba M (1985) Inhibition by aminohydroxy-propylidene bisphosphonate (AHPrBP) of 1,25(OH)2 vitamin D3-induced stimulated bone turnover in the mouse. Calcif Tissue Int 37:268–275 [DOI] [PubMed] [Google Scholar]
  24. Martodam RR, Johnson KJ, Jung A (1981) The effects of diphosphonates (bone seeking agents) on hypercalcemia and increased bone resorption in the rat Walker 256 tumor and in humans. Breast Cancer 1(2):165 [Google Scholar]
  25. Meunier PJ, Chapuy M, Delmas P, Charhon S, Edouard C, Arlot M (1987) Intravenous disodium etidronate therapy in Paget's disease of bone and hypercalcemia of malignancy. Am J Med 82:71–78 [DOI] [PubMed] [Google Scholar]
  26. Morton AR, Pillai GV, Cantrill J, Howell A (1988) Sclerosis of lytic bone metastases during treatment with aminohydroxypropylidene diphosphonate (APD): a healing response? Br J Cancer 58(2):259 [Google Scholar]
  27. Münch H (1988) Synthese und Untersuchung von osteotropen Platinkomplexen. Dissertation Thesis, University Heidelberg
  28. Reitsma HP, Bijvoet OLM, Potokar M, van der Wee-Pals LJA, van Wijk-van Lennep MML (1983) Apposition and resorption of bone during oral treatment with (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD). Calcif Tissue Int 35:357–361 [DOI] [PubMed] [Google Scholar]
  29. Samuel AW, Rushton S, Galasko CS (1979). Effects of prostaglandin inhibitors and diphosphonates on tumor mediated osteolysis. Br J Surg 66:901 [DOI] [PubMed] [Google Scholar]
  30. Schenk R, Eggli P, 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 [DOI] [PubMed] [Google Scholar]
  31. Scher HI, Yagoda A (1987) Bone metastasis: pathogenesis, treatment, and rationale for use of resorption inhibitors. Am J Med 82:6–28 [DOI] [PubMed] [Google Scholar]
  32. Sleeboom HP, Bijvoet OLM, van Osterom AT, Gleed JH, O'Riordan JL (1983) Comparison of intravenous (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate and volume repletion in tumor-induced hypercalcemia. Lancet II:239–243 [DOI] [PubMed] [Google Scholar]
  33. Wingen F, SchmÄhl D (1985) Distribution of 3-amino-1-hydroxypropane-1,1-diphosphonic acid in rats and effects on rat osteosarcoma. Drug Res 35:1565–1571 [PubMed] [Google Scholar]
  34. Wingen F, SchmÄhl D, Berger MR, Spring H (1984) Intraosseously transplantable osteosarcoma with regularly disseminating pulmonary metastases in rats. Cancer Lett 23:201–211 [DOI] [PubMed] [Google Scholar]
  35. Wingen F, Eichmann T, Manegold C, Krempien B (1986a) Effects of new bisphosphonic acids on tumor-induced bone destruction in the rat. J Cancer Res Clin Oncol 111:35–46 [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Wingen F, Sterz H, Blum H, Möller H, Pittermann W, Pool BL, Sinn HJ, Spring H, SchmÄhl D (1986b) Synthesis, antitumor activity, distribution and toxicity of 4-[4-[bis(2-chloroethyl)amino]phenyl]-1-hydroxybutane-1,1-bisphosphonate (BAD), a new lost derivative with increased accumulation in rat osteosarcoma. J Cancer Res Clin Oncol 111:209–219 [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Wingen F, Spring H, SchmÄhl D (1987) Antimetastatic effects of razoxane in a rat osteosarcoma model. Clin Exp Metastasis 5:9–16 [DOI] [PubMed] [Google Scholar]

Articles from Journal of Cancer Research and Clinical Oncology are provided here courtesy of Springer

RESOURCES