Summary
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.
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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
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
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
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
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
Canfield RE (1987) Rationale for disphosphonate therapy in hypercalcemia of malignancy. Am J Med 82:1–5
Coleman RE, Rubens RD (1987) 3(Amino-1,1-hydroxypropylidene) bisphosphonate (APD) for hypercalcemia of breast cancer. Br J Cancer 56:465–469
Fogelman I (1982) Diphosphonate bone scanning agents — current concepts. Eur J Nucl Med 7:506–509
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
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
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
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
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
Jung A (1982) Comparison of two parenteral diphosphonates in hypercalcemia of malignancy. Am J Med 72:221–226
Kalbfleisch JD, Prentice RE (1980) The statistical analysis of failure time data. Wiley, New York
Kanis JA (ed) (1987) Clodronate — a new perspective in the treatment of neoplastic bone disease. Bone 8 [Suppl 1]
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
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
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
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
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
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
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
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
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
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
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
Münch H (1988) Synthese und Untersuchung von osteotropen Platinkomplexen. Dissertation Thesis, University Heidelberg
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
Samuel AW, Rushton S, Galasko CS (1979). Effects of prostaglandin inhibitors and diphosphonates on tumor mediated osteolysis. Br J Surg 66:901
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
Scher HI, Yagoda A (1987) Bone metastasis: pathogenesis, treatment, and rationale for use of resorption inhibitors. Am J Med 82:6–28
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
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
Wingen F, SchmÄhl D, Berger MR, Spring H (1984) Intraosseously transplantable osteosarcoma with regularly disseminating pulmonary metastases in rats. Cancer Lett 23:201–211
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
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
Wingen F, Spring H, SchmÄhl D (1987) Antimetastatic effects of razoxane in a rat osteosarcoma model. Clin Exp Metastasis 5:9–16
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Klenner, T., Wingen, F., Keppler, B.K. et al. Anticancer-agent-linked phosphonates with antiosteolytic and antineoplastic properties: a promising perspective in the treatment of bone-related malignancies?. J Cancer Res Clin Oncol 116, 341–350 (1990). https://doi.org/10.1007/BF01612916
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DOI: https://doi.org/10.1007/BF01612916