Summary
This study primarily describes the cytostatic activity of a bisphosphonate and of an alkylating agent linked bisphosphonate toward mammary carcinomas in vivo. Bisphosphonates had been shown to be therapeutically active in bone metastases. There is no animal tumor model available in which both primary mammary carcinomas and bone metastases can be studied simultaneously. Therefore, the Walker carcinosarcoma model, which was used as a model for bone metastasis in earlier studies, was combined with the M-methyl-N-nitrosourea (MNU) induced mammary carcinoma as a model for the primary tumor. Four-, or six-week treatment of MNU-induced mammary carcinomas in Sprague-Dawley rats with the new aromatic bisphosphonate 4[4-[bis(2-chloroethyl)-amino]-phenyl]-1-hydroxybutane-1,1-bisphosphonate (BAD) showed higher antitumor activity than treatment with melphalan or with 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (APD) alone. BAD is the APD moiety covalently bound to a molecule derived from melphalan. A combination therapy with 11.75 mg/kg/day APD and 0.6 mg/kg/day melphalan showed the best therapeutic efficacy in this tumor model. In comparison to monotherapy with BAD, APD, or melphalan, a significantly higher rate of complete remissions was achieved. APD, itself, was not genotoxic in 3 employed short term assays. Since bisphosphonates had been shown to be therapeutically active in bone metastases, the antitumor potency of these compounds against experimental primary mammary carcinomas, coupled with the non-genotoxicity of APD and the inhibition of osteolytic bone metastases, might be an important advancement for adjuvant chemotherapy of human mammary carcinomas.
Similar content being viewed by others
References
Fogelman I: Diphosphonate bone scanning agents — Current concepts. Eur J Nucl Med 7:506–509, 1982
Frijlink WB, Bijvoet OLM, te Velte J, Heynen G: Treatment of Paget's disease with (3-amino-1-hydroxypropyl-idene)-1,1-bisphosphonate (A.P.D.). Lancet I:799–803, 1979
Heaney RP, Saville PD: Etidronate disodium in postmenopausal osteoporosis. Clin Pharmacol Ther 20:593–604, 1976
Jung A, Fleisch H: Les disphosphonates dans le traitement des metastases osseuses. Schweiz Med Wochenschr 111: 1878–1882, 1981
Jung A: Comparison of two parenteral disphosphonates in Hypercalcemia of malignancy. Am J Med 72:221–226, 1982
Delamore IW: Hypercalcaemia and myecloma. Br J Haematol 51:507–509, 1982
Krempien B, Pfeilschifter J, Minne H: 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, 1982, pp 117–122
Felix R, Fleisch H: The effect of disphosphonates on periostal and bone cells in culture. Experientia 37:817–819, 1981
Schnur W: Palliative apin therapy among bone metastases. Arzneimitteltherapie 4:128, 1984
Radl J, Croese JW, Zurcher C: Influence of treatment with APD-Bisphosphonate on the bone lesions in the mouse 5T2 multiple myeloma. Cancer 55:1030–1040, 1985
Wingen F, Schmähl D: Distribution of 3-Amino-1-hydroxypropane-1,1-diphosphonic acid (APD) in rats and effects on rat osteosarcoma. Arzneimittelforschung 35 (II):1565–1571, 1985
Guaitani A, Polentarutti N, Filippeschi S, Marmoti L, Corti F, Italia C, Coccioli G, Donelli MG, Mantovani A, Gerattini S: Effects of disodium etidronate in murine tumor models. Eur J Cancer Clin Oncol 20:685–693, 1984
Wingen F, Eichmann T, Manegold C, Krempien B: Effects of new bisphosphonic acids on tumor-induced bone destruction in the rat. J Cancer Res Clin Oncol 111:35–41, 1986
Krempien B, Wingen F, Eichmann T, Müller M, Schmähl D: 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, 1988
Zeller WJ, Berger MR: Chemically induced autochthonous tumor models in experimental chemotherapy. Behring Inst Mitt 74:201–208, 1984
Pool BL, Eisenbrand G, Preussmann R, Schlehofer JR, Schmezer P, Weber H, Wießler M: Detection of mutations in bacteria, as well as DNA damage and amplified DNA sequences in mammalian cells as a systematic test strategy for elucidating biological activities of chemical carcinogens. Fd Chem Toxic 24:685–691, 1986
Pool BL, Weber H, Schlehofer JR: Induction of SV40 DNA amplification in SV40 transformed hamster cells. Limitations and capacities of a new short term test system for analysis of chemical carcinogens. Accomplishments in Oncology, Volume 2. The role of DNA amplification in Carcinogenesis. J.G. Fortner, H. zur Hausen and J.R. Schlehofer (eds) Philadelphia, J.B. Lippincott Company, 1987, pp 198–210
Schimke RT: Gene amplification in cultured animal cells. Cell 37:705–713, 1984
Schmähl D: Carcinogenicity of anticancer drugs and especially alkylating agents. In: D Schmähl and HJ Kaldor (ed) Carcinogenicity of Alkylating Cytostatic Drugs (IARC Scientific Publications No 78, 1986) Lyon, International agency for research on Cancer.
Ames BN, McCann J, Yamasake E: Methods for detecting carcinogens and mutagens with the Salmonella/mammalian microsome mutagenicity test. Mutation Res 31:347–364, 1975
Sina JF, Bean CL, Dysart GR, Taylor VI, Bradley MO: Evaluation of the alkaline elution/rat hepatocyte assay as a predictor of carcinogenic/mutagenic potential. Mutation Res 113:357–391, 1983
Lavi S: Carcinogen-mediated activation of SV40 replicons: A model system for initiation of carcinogenesis. In: Shimke RD (ed) Gene Amplification Cold Spring Harbor Laboratory:225–230, 1982
Wingen F, Sterz H, Blum H, Möller H, Pittermann W, Pool BL, Sinn HJ, Spring H and Schmähl D: 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
Wingen F, Schmähl D: Pharmacokinetics of the osteotropic diphosphonate 3-Amino-1-hydroxypropane-1,1-diphosphonic acid in mammals. Drug Res 37 (11), 9, 1037–1042, 1987
Koziol AJ, Donna AM: A distribution-free test for tumor growth curve analysis with application to an animal tumor immunotherapy experiment. Biometrics 37, 383–390, 1981
Kalbfleisch JD, Prentice RE (1980) The statistical analysis of failure time data. New York, Wiley
Maron D, Katzenellenbogen J, and Ames BN: Compatibility of organic solvents with the Salmonella/microsome test. Mutation Res 88:343–350, 1981
Pool BL, and Lin PZ: “Mutagenicity testing of phenolic compounds and phenolic fractions obtained from smoke-house smoke condensate in the Salmonella typhimurium assay.” Food Chem Toxicol 20:383–391, 1982
Bradley MO, Dysart G, Fitzsimmons K, Harbach R, Lewin J, Wolf G: Measurements by filter elution of DNA single and double strand breaks in rat hepatocytes: Effects of nitrosamines and irradiation. Cancer 42:2592–2597, 1982
Romruen K, Pool BL: Metabolic activation capabilities of S9 and hepatocytes from uninduced rats to convert carcinogenic N-nitrosamines to mutagens. Mutation Res 140: 147–153, 1984
Kohn KW: DNA as a target in cancer chemotherapy: measurement of macromolecular DNA damage produced in mammalian cells by anticancer agents and carcinogens. In: Methods in Cancer Research, Vol 16 Academic Press, Inc., 1979, pp 291–345
Kohn KW, Ewig RAG, Erickson LC, Zwelling LA: Measurement of strand breaks and cross-links by alkaline elution. In: Friedberg EC, Hanawalt PC, Volume 1, Marcel Dekker (eds) DNA repair, a Laboratory Manual of Research Procedures New York, NY 1981, vol 1:379–401
Lavi S, Etkin S: Carcinogen-mediated induction of SV40 DNA synthesis in SV40 transformed Chinese hamster embryo cells. Carcinogenesis 2:417–423, 1981
Petru E, Schmähl D: Bedeutung der Zusammensetzung verschiedener Kombinationsschemata bei der Chemotherapie des metastasierenden Mammacarcinoms. Dtsch med Wschr 112:270–275, 1987
Pool BL, Schmähl D: What's new in mutagenicity and carcinogenicity — Status of short term assay systems as tools in genetic toxicology and carcinogenesis. Path Res Pract 182:704–712, 1987
Harper BL, Rinkus SJ, Scott M, Ammenhauser M, Bang KM, Lowery M and Legator MS: The use of human cells for the evaluation of risk from physical and chemical agents. In: Ameleto Castallani (ed) Correlation of NCI and IARC carcinogens with their mutagenicity in Salmonella. Nato advanced Sc Institutes Series V. 60, Plenum Press NY 1983, pp 353–419
Pool B, Berger M, Schlehofer J, Wingen F: In vivo and in vitro investigations on biological effects of aromatic Bis-(2-chloroethyl)amino-bisphosphonic acids, new agents proposed for chemotherapy of bone tumors: Cytostatic activity in rat osteosarcoma; toxicity and genotoxicity in liver and bone marrow; mutagenicity in S. typhimurium. Invest New Drugs 6:67–78, 1988
IARC Monographs, Suppl. 4, pp 154–155 (1982)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Wingen, F., Pool, B.L., Klein, P. et al. Anticancer activity of bisphosphonic acids in methylnitrosourea-induced mammary carcinoma of the rat — benefit of combining bisphosphonates with cytostatic agents. Invest New Drugs 6, 155–167 (1988). https://doi.org/10.1007/BF00175392
Issue Date:
DOI: https://doi.org/10.1007/BF00175392