Skip to main content
SpringerLink
Log in

Synthesis, antitumor activity, distribution and toxicity of 4-[4-[Bis(2-chloroethyl)amino]phenyl]-1-hydroxybutane-1 1-bisphosphonic acid (BAD), a new lost derivative with increased accumulation in rat osteosarcoma

  • Original Papers
  • Experimental Oncology
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Summary

The aim of this study was to investigate whether the newly synthesized bisphosphonic acidlinked N-Lost derivative BAD retains bone-seeking and cytostatic properties. The paper describes experiments on mutagenicity in vitro and on toxicity in vivo. BAD is characterized by very low mutagenic activity toward histidine auxotrophic Salmonella typhimurium strains. Cytotoxic effects were tested in rat osteosarcoma and in Walker carcinosarcoma 256B. The LD50 of i.v. injected BAD was 146 mg/kg. Acute toxicity is probably caused by calcium complexing of the bisphosphonate part of the molecule. Labeling experiments showed moderate accumulation in bone and osteosarcoma, as well as in lung metastases. BAD effected high tumor growth inhibition in osteosarcoma and Walker carcinosarcoma-bearing rats and marked prolongation of survival; histologic and radiographic examination revealed rapid calcification of osteosarcoma and lung metastases. BAD-pretreatment produced protective effects against osteolysis induced by intratibially implanted Walker carcinosarcoma ascites cells. The cytostatic efficacy of equitoxic doses of BAD in rat osteosarcoma is comparable to that of dacarbazine and in Walker carcinosarcoma to that of melphalan.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Ames BN, McCann J, Yamasaki E (1975) Methods for detecting carcinogens and mutagens with the Salmonella/mammalian-microsome mutagenicity test. Mutat Res 31:347–364

    Article  PubMed  Google Scholar 

  • Benedict WF, Baker MS, Haroun L, Choi E, Ames BN (1977) Mutagenicity of Cancer Chemotherapeutic. Agents in the Salmonella/Microsome Test. Cancer Res 37:2209–2213

    PubMed  Google Scholar 

  • Bolognose C, Cesarone CF, Santi L (1979) Standardization of alkaline elution procedure using X-ray damaged nuclear DNA. Tumori 65:511–516

    PubMed  Google Scholar 

  • Canfield R, Rosner W, Skinner J, McWhorter J, Resnick L, Feldman F, Kammerman S, Ryan K, Kunigonis M, Bohne W (1977) Diphosphonate therapy of Pagets' disease in bone. I. Clin Endocrinol Metab 44:96–109

    Google Scholar 

  • Cavalli-Sforza L (1974) Biometrie — Grundzüge biologischer medizinischer Statistik 6. Fischer Verlag, Stuttgart, pp 33–34

    Google Scholar 

  • Delamore IW (1982) Hypercalcaemia and mycloma. Br J Haematol 51:507–509

    PubMed  Google Scholar 

  • Delbrück HG, Allouche H, Jasmin C, Morin M, Deml F, Aughilers L, Masse R, Lafuma I (1980) Bone tumors induced in rats with radioactive cerium. Br J Cancer 41:809–815

    PubMed  Google Scholar 

  • Delbrück H, Nell G, Arf A, Thiel H, Reikowski H, Siepmann H (1982) Ultrasonographic evaluation of structure, histology, kinetics and early chemotherapeutic response in tumors (abstract). Blut 45:221

    Google Scholar 

  • Delbrück H (1982) Experimentelle Untersuchungen an einem Osteosarkommodell. Habilitationsschrift, Homburg/Saar

  • Eisenhut M, Berberich R, Kimmig B, Wingen F, Georgi P, Oberhausen E, zum Winkel K (1985) Line 131J-markierte Benzylidendiphosphonsäure für die palliative Therapie von Knochenmetastasen: Kinetik und Wirkung 2. Tübinger Knochensymposium 11–12 Jan 1985, Tübingen, FRG

  • Felix R, Fleisch H (1981) The effect of diphosphonates on periostal and bone cells in culture. Experientia 37:817–819

    PubMed  Google Scholar 

  • Fogelman I (1982) Diphosphonate bone scanning agents — Current concepts. Eur J Nucl Med 7:506–509

    PubMed  Google Scholar 

  • Frijlink WB, Bijvoet OLM, te Velte J, Heynen G (1979) Treatment of Paget's disease with (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (A.P.D.). Lancet I:799–803

    Article  Google Scholar 

  • Guaitani A, Polentarutti N, Filippeschi 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

    Article  PubMed  Google Scholar 

  • Guilland DF, Sallis ID, Fleisch H (1974) The effect of two diphosphonates on the handling of calcium by rat kidney mitochondria in vitro. Calcif Tissue Res 15:303–314

    PubMed  Google Scholar 

  • Habs M (1980) Methoden, Ergebnisse und Probleme der experimenteller Chemotherapie. In: Schmähl D (Hrsg) Maligne Tumoren, Entstehung, Wachstum, Chemotherapie. Editio Cantor Aulendorf p 467

  • Habs M, Habs H (1980) Durchführung und Auswertung von Tierversuchen zur Cancerogenese. In: Schmähl D (Hrsg) Maligne Tumoren. Editio Cantor Aulendorf (3rd ed) pp 42–47

  • Heaney RP, Saville PD (1976) Etidronate disodium in postmenopausal osteoporosis. Clin Pharmacol Ther 20:593–604

    PubMed  Google Scholar 

  • Heins A, Plöger W (1980) Henkel-Referate 16, Excerpts of Henkel Research Papers, 19–25. Henkel Chemical Corp., 600, Madison Avenue, New York, NJ 20022

    Google Scholar 

  • Hensel H, Schäfer K (1974) Effects of calcium on warm and cold receptors. Pflügers Arch 352:87

    Google Scholar 

  • IARC International Agency for Research on Cancer (1982) Chemicals, industrial processes and industries associated with cancer in humans, IARC, Lyons (IARC monographs on the evaluation of the carcinogenic risk of chemicals to human, supplement)

    Google Scholar 

  • Jung A, Fleisch H (1981) Les diphosphonates dans le traitement des metastases osseuses. Schweiz Med Wochenschr 111:1878–1882

    PubMed  Google Scholar 

  • Jung A (1982) Comparison of two parenteral diphosphonates in Hypercalcemia of malignancy. Am J Med 72:221–226

    Article  PubMed  Google Scholar 

  • Krempien B, Pfeilschifter J, Minne H (1982) Influence of (3-Amino-1-Hydroxypropylidene)-1,1-bisphosphonate (APD) on bone remodelling. In: Silverman (ed) Current advances in sceletogenesis. HC Slavkin, Amsterdam, Oxford, Privetion, pp 117–122

    Google Scholar 

  • Loehrke H, Hesse B (1981) Das Walker Ca 256 auf der SD-Ratte. Tumorsteckbrief, Deutsches Krebsforschungszentrum Heidelberg, Institut für experimentelle Pathologie, Tumorbank

    Google Scholar 

  • Menge M (1983) Hemmung der Knochengewebsbildung durch Propan-2,2-diphosphonat. Fortschr Med 39:1787–1791

    Google Scholar 

  • Miune H, Ziegler R, Schmitt W, Hilgard P (1971) Die hypercalcämische Aktivität des Walker-Karzinosarkoms 256 bei der Ratte. Schweiz Med Wochenschr 101:481

    PubMed  Google Scholar 

  • Mundy GP (1980) Osteoclasts activating factors. Metab Bone Dis Relat Res 2:172

    Google Scholar 

  • Nakashima H, Ochi H, Yasni N, Hamada H, Ono K (1982) Uptake and localisation of 99mTc-Methylene-Diphosphonate in mouse osteosarcoma. Eur J Nucl Med 7:531–535

    PubMed  Google Scholar 

  • Plasmans CMT, Jap PHK, Kuijpers W, Slooff TJJH (1980) Influence of diphosphonate on the cellular aspect of young bone tissue. Calcif Tissue Int 32:247–256

    PubMed  Google Scholar 

  • Pool BL, Röper H, Röper S, Romruen K (1984) Mutagenicity studies on N-nitrosated products of the maillard browning reaction. N-nitroso-fructose-amino acids. Food Chem Toxicol 22:797–801

    Article  PubMed  Google Scholar 

  • Radl J, Croese JW, Zurcher C et al. (1985) Influence of treatment with APD-Bisphosphonate on the bone lesions in the mouse 5T2 multiple myeloma. Cancer 55:1030–1040

    PubMed  Google Scholar 

  • Rieche K (1984) Carcinogenicity of antineoplastic agents in man. Cancer Treat Rev 11:39–67

    Article  Google Scholar 

  • Saackel LR (1974) Elektronische Auswertung von Mikroradiogrammen. Biomed Tech 19:10–14

    Google Scholar 

  • Schmähl D, Habs M, Lorenz M, Wagner I Occurrence of second tumors in man after anticancer drug treatment. Cancer Treat Rev 9:167–194

  • Schnur W (1984) Palliative pain therapy among bone metastases. Arzneimitteltherapie 4:128

    Google Scholar 

  • Senekowitsch R, Kriegel H (1980) Der Einfluß einer Chemotherapie auf die Retention von 99mTc-Methylendiphosphonat im Osteosarkom der Maus. Nucl Med 19(4):200–205

    Google Scholar 

  • Sterz H, Hebold G (1980) Analysis of radiographs in reproduction toxicology by means of densitometry and planimetry. In: Merker HJ, Nau H, Neubert D (eds) Teratology of the limbs. De Gruyter, Berlin, pp 373–382

    Google Scholar 

  • Ther L (1965) In: Grundlagen der experimentellen Arzneimittelforschung. Wiss. Verlagsgesellschaft Stuttgart, pp 82–95

    Google Scholar 

  • Weber E (1980) Adam — Statistische Auswertung biomedizinischer Daten. Teil I. Deutsches Krebsforschungszentrum, Heidelberg

    Google Scholar 

  • Weber E (1982) Survival — Statistische Auswertung biomedizinischer Daten. Teil II. Deutsches Krebsforschungszentrum, Heidelberg

    Google Scholar 

  • Wingen F, Schmähl D, Berger MR, Spring H (1984) Intraosseously transplantable osteosarcoma with regulary disseminating pulmonary metastases in rats. Cancer Lett 23:201–211

    Article  PubMed  Google Scholar 

  • Wingen F, Schmähl D (1985) Distribution of 3-Amino-1-hydroxypropane-1,1-diphosphonic Acid (APD) in rats and effects on rat osteosarcoma. Arzneimittelforschung 35(II), 1565–1571

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Toxicology and Chemotherapy, German Cancer Research Center, Im Neuenheimer Feld 280, D-6900, Heidelberg, Federal Republic of Germany

    F. Wingen, B. L. Pool & D. Schmahl

  2. Institute of Nuclear Medicine, German Cancer Research Center, D-6900, Heidelberg

    H. J. Sinn

  3. Institute of Experimental Pathology, German Cancer Research Center, D-6900, Heidelberg

    H. Spring

  4. Department of Medical Research, Boehringer Mannheim GmbH, D-6800, Mannheim, Federal Republic of Germany

    H. Sterz

  5. Henkel KGaA, D-4000, Düsseldorf, Federal Republic of Germany

    H. Blum, H. Möller & W. Pittermann

Authors
  1. F. Wingen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H. Sterz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H. Blum
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H. Möller
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. W. Pittermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B. L. Pool
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H. J. Sinn
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H. Spring
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. D. Schmahl
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Dedicated to Professor P. Obrecht, Basel, on the occasion of his 60th birthday

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wingen, F., Sterz, H., Blum, H. et al. Synthesis, antitumor activity, distribution and toxicity of 4-[4-[Bis(2-chloroethyl)amino]phenyl]-1-hydroxybutane-1 1-bisphosphonic acid (BAD), a new lost derivative with increased accumulation in rat osteosarcoma. J Cancer Res Clin Oncol 111, 209–219 (1986). https://doi.org/10.1007/BF00389236

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00389236

Key words

Search

Navigation