Cancer Chemotherapy and Pharmacology

, Volume 32, Issue 1, pp 25–30 | Cite as

Reversal of multidrug resistance in friend leukemia cells by dexniguldipine-HCl

  • Andreas Reymann
  • Guido Looft
  • Cornelia Woermann
  • Manfred Dietel
  • Rudolf Erttmann
Original Articles Multidrug Resistance, Modulators, Cytostatic Drug Disposition

Abstract

Dexniguldipine-HCl (DNIG) — a prospective clinical modulator of p170-glycoprotein (pgp170)-mediated multidrug resistance (MRD) — was evaluated in a drug-accumulation assay in MDR murine leukemia cell strain F4-6RADR expressing pgp170. The compound elevated low accumulation of either doxorubicin (DOX), daunorubicin (DNR), or mitoxantrone (MITO) in resistant F4-6RADR cells to the very levels observed in drug-sensitive F4-6 precursor cells. In parallel with the increase in DNR content (F4-6RADR, solvent: 303±27 pmol/mg protein; DNIG (3.3 μmol/l): 1,067±174 pmol/mg protein; F4-6P, solvent: 948±110 pmol/mg protein;n=8–9, SEM), the amount of DNR tightly bound to the acid precipitate pellet obtained from F4-6RADR (i.e., protein, DNA, RNA) increased 3.9-times to the levels observed in sensitive F4-6 cells. The main pyridine metabolite of DNIG displayed similar activity. Concentration-response analysis revealed that DNIG and R,S-verapamil (VER) induced 100% reversal of the DNR accumulation shortage associated with the MDR phenotype but DNIG was 8 times more potent than VER (50% inhibitory concentration (IC50), 0.73 vs 5.4 μmol/l). In keeping with the accumulation assay, DNIG was about 10 times more potent than VER in sensitizing F4-6RADR cells to the cytostatic and cytotoxic effects of DNR in proliferation assays. In conclusion, DNIG is a potent in vitro modulator, improving (a) the accumulation of anthracycline-like cytostatics, (B) drug access to cellular binding sites, and (c) the cytostatic action of DNR in F4-6RADR leukemia cells of the MDR phenotype.

Keywords

Doxorubicin Leukemia Cell Multidrug Resistance Mitoxantrone Daunorubicin 

Abbreviations

DOX

doxorubicin

CSA

cyclosporin A

DMSO

dimethylsulfoxide

DNIG

dexniguldipine-HCl

DNR

daunorubicin

MDR

multidrug resistance

MITO

mitoxantrone

pgp170

permease glycoprotein 170

VER

R.S.-verapamil

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References

  1. 1.
    Beck WT (1991) Modulators of P-glycoprotein-associated multidrug resistance. In: Ozols RF (ed) Molecular and clinical advances in anticancer drug resistance. Kluwer, Boston, p 151Google Scholar
  2. 2.
    Bradford M (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248Google Scholar
  3. 3.
    Dietel M (1992) What's new in cytostatic drug resistance. Pathol Res Pract 187: 892Google Scholar
  4. 4.
    Dietel M, Arps H, Lage H, Niendorf A (1990) Membrane vesicle formation due to acquired mitoxantrone resistance in human gastric carcinoma cell line EPG85-257. Cancer Res 50: 6100Google Scholar
  5. 5.
    Dietel M, Bunge A, Heidebrecht HJ, Reymann A, Seidel A (1992) Resistance to the Adriamycin resistance reversing potency of cyclosporin A in P-glycoprotein positive Friend leukemia cells. Proc Am Assoc Cancer Res 33: 486Google Scholar
  6. 6.
    Drozd MP, Gietzen K (1990) Effects of the novel dihydropyridine derivative niguldipine on the cytoplasmic free calcium concentration of mouse thymocytes. Biochem Pharmacol 40: 955Google Scholar
  7. 7.
    Erttmann R, Boetefür A, Erttmann KD, Gieseler F, Looft G, Münchmeyer M, Reymann A, Winkler K (1992) Conserved cytotoxic activity of aclacinomycin A in multifactorial drug resistance. In: Hiddemann E (ed) Haematology and blood transfusion, vol 34. Acute leukemias — pharmacokinetics. Springer, Berlin Heidelberg New York, p 49Google Scholar
  8. 8.
    Friend C, Patuleia MC, Harven E de (1966) Erythrocytic maturation in vitro of murine Friend-virus induced leukemic cells. NCI Monogr 22: 505Google Scholar
  9. 9.
    Häussermann K, Benz B, Roller E, Gekeler V, Schumacher K, Eichelbaum M (1990) Cytotoxic effects of the new Ca++/calmodulin antagonist B859-35 on sensitive and MDR cell lines (abstract). J Cancer Res Clin Oncol 116: A4.114.30Google Scholar
  10. 10.
    Hoffmann D, Berscheid HG, Böttger D, Hermentin P, Sedlacek HH, Kraemer HP (1990) Structure-activity relationship of anthracyclines in vitro. J Med Chem 33: 166Google Scholar
  11. 11.
    Hofmann J, Ueberall F, Egle A, Grunicke H (1991) B859-35, a new drug with antitumor activity reverses multidrug resistance. Int J Cancer 47: 870Google Scholar
  12. 12.
    Hofmann J, Wolf A, Spitaler M, Böck G, Drach J, Ludescher C, Grunicke H (1992) Reversal of multidrug resistance by B859-35, a metabolite of B859-35, niguldipine, verapamil and nitrendipine. J Cancer Res Clin Oncol 118: 361Google Scholar
  13. 13.
    Hu XF, Martin TJ, Bell DR, Luise M de, Zalcherg J (1990) Combined use of cyclosporin A and verapamil in modulating multidrug resistance in human leukemia cell lines. Cancer Res 50: 2953Google Scholar
  14. 14.
    Karck U, Rathgeb F, Wurst W, Meerpohl HG (1992) Open phase I/II study of standard FEC therapy with B8509-35, a novel drug blocking the p-170 glycoprotein (abstract 85). Proceedings, 7th NCI-EORTC Symposium on New Drugs in Cancer Chemotherapy, Amsterdam, March 17th–20th, 1992Google Scholar
  15. 15.
    Louie KG, Hamilton TC, Winker MA, Behrens BC, Tsuruo T, Klecker, RW Jr, McKoy WM, Grotzinger KR, Myers CE, Young RC, Ozols RF (1986) Adriamycin accumulation and metabolism in Adriamycin-sensitive and-resistant human ovarian cancer cell lines. Biochem Pharmacol 35: 467Google Scholar
  16. 16.
    Myers CE, Chabner BA (1990) Anthracyclines. In: Chabner BA, Collins JM (eds) Cancer chemotherapy: principles and practice. J.B. Lippincott, Philadelphia, p 356Google Scholar
  17. 17.
    N.N. (1992) Drugs reverse resistance to anticancers. SCRIP 1708: 22Google Scholar
  18. 18.
    Ozols RF, Cunnion RE, Klecker RW Jr, Hamilton TC, Ostchenga Y, Parillo JE, Young RC (1987) Verapamil and Adriamycin in the treatment of drug resistant ovarian cancer patients. J Clin Oncol 5: 641Google Scholar
  19. 19.
    Peters W, Ekong R, Robinson BL, Warhurst DC, Pan XQ (1989) Antihistaminic drugs that reverse chloroquine resistance inPlasmodium falciparum. Lancet II: 334Google Scholar
  20. 20.
    Reymann A, Woermann C (1989) In vitro study on physiological membrane transport and diffusional properties in multidrug-resistant mouse Friend erythroleukemia cells. Naunyn Schmiedebergs Arch Pharmacol 339: R42Google Scholar
  21. 21.
    Reymann A, Edens L, Erb N, Erttmann R, Looft G, Woermann C (1989) Steady state kinetics of anthracycline uptake in mouse Friend erythroleukemia cells. Naunyn Schmiedebergs Arch Pharmacol 340: R78Google Scholar
  22. 22.
    Reymann A, Woermann C, Dietel M (1991) Reversal of anthracycline accumulation deficits in multidrug resistant Friend leukemia cells by the dihydropyridine B859-35, the R-enantiomer of niguldipine. Naunyn Schmiedebergs Arch Pharmacol 343: R50Google Scholar
  23. 23.
    Reymann A, Dörner C, Erttmann R, Looft G, Woermann C, Dietel M (1992) Chemosensitizer properties of cyclosporin A in multidrug resistant Friend leukemia cells. Naunyn Schmiedebergs Arch Pharmacol 345: R65Google Scholar
  24. 24.
    Schuller HM, Correa E, Orloff M, Reznik GK (1990) Successful therapy of experimental neuroendocrine lung tumors in hamsters with an antagonist of Ca++/Calmodulin. Cancer Res 50: 1645Google Scholar
  25. 25.
    Schuurhuis GJ, Broxtermann HJ, Cervantes A, Van Heiningen TH, Lange JH de, Baak JD, Pinedo HM (1989) Quantitative determination of factors contributing to doxorubicin resistance in multidrug resistant cells. J Natl Cancer Inst 81: 1887Google Scholar
  26. 26.
    Steinhoff A, Boetefür A, Looft G, Erttmann R (1989) Immunocytochemical detection of p170-glycoprotein in multidrug-resistant and superresistant mouse leukemia cells. Naunyn Schmiedebergs Arch Pharmacol 340: R50Google Scholar
  27. 27.
    Tallarida RJ, Murray RB (1987) Manual of pharmacologic calculations with computer programs, 2nd edn. Springer, New York Berlin Heidelberg London Paris TokyoGoogle Scholar
  28. 28.
    Tsuruo T, Kawabata H, Nagumo N, Iida H, Kitatani Y, Tsukagoshi S, Sakurai Y (1985) Potentiation of antitumor agents by calcium channel blockers with special reference to cross-resistance patterns. Cancer Chemother Pharmacol 15: 16Google Scholar
  29. 29.
    Überall F, Maly K, Egle A, Doppler W, Hofmann J, Grunicke H (1991) Inhibition of cell proliferation, protein kinase C and phorbol ester-inducedfos expression by the dihydropyridine derivative B859-35. Cancer Res 51: 5821Google Scholar
  30. 30.
    Vries EGE de, Pinedo HM (1991) Clinical implications of multidrug resistance to chemotherapy. In: Ozols RF (ed) Molecular and clinical advances in anticancer drug resistance. Kluwer, Boston, p 171Google Scholar
  31. 31.
    Werdan K, Lehner K, Cremer T, Stevenson AFG, Messerschmidt O (1980)d-Glucose transport into suspended human fibroblasts. Rapid measurement of uptake by silicone oil filtration centrifugation and comparison of different cell detachment procedures. Hoppe-Seylers Z Physiol Chem 361: 91Google Scholar
  32. 32.
    Wolf M, Lenze H, Schroeder M, Maasberg M, Wurst W, Rathgeb F, Havemann K (1991) Application of the dihydropyridine derivative B8509-35 in resistant small cell lung cancer. Eur J Cancer 27 [Suppl 2]: R1128Google Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • Andreas Reymann
    • 1
  • Guido Looft
    • 2
  • Cornelia Woermann
    • 1
  • Manfred Dietel
    • 3
  • Rudolf Erttmann
    • 2
  1. 1.Abteilung für Allgemeine PharmakologieUniversitäts-Krankenhaus EppendorfHamburg 20Germany
  2. 2.Abteilung für Pädiatrische Hämatologie und OnkologieUniversitäts-Krankenhaus EppendorfHamburg 20Germany
  3. 3.Institut für PathologieChristian-Albrechts-Universität zu KielKiel 1Germany

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