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Selectivity of the anthracyclines for negatively charged model membranes: role of the amino group

  • Original Articles
  • Anthracycline, Membrane Interaction
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Summary

The equilibrium-binding affinities of six adriamycin analogues and four daunomycin derivatives for negatively charged dimyristoyl phosphatidylcholine/dimyristoyl phosphatidic acid (DMPC/DMPA) small unilamellar vesicles are compared with values for electroneutral DMPC liposomes. Binding of the daunomycin series to negatively charged dimyristoyl phosphatidyl glycerol (DMPG) vesicles was also examined. Under physiological conditions of pH and ionic strength, substitution of the amino group of adriamycin or daunomycin resulted in a reduced affinity for negatively charged bilayers, even if the substituent enhanced the degree of ionization of the amine. Decreasing the ionic strength increases the binding affinity for acidic membranes but decreases the drug affinity for neutral membranes. We propose that the electrostatic bond of the phosphate-amino group that has been shown to exist between anthracyclines and phosphatidic acid is sterically destabilized by substitution of the amino group. The results are consistent with a mode of anthracycline binding to negatively charged membranes which is driven by hydrophobic and electrostatic considerations but is destabilized by steric bulk at the amino group. THe data also provide insight into the design of new anthracyclines with high membrane affinities and reduced uptake; such directed interaction with plasma membranes may enhance antineoplastic potential while reducing cardiac toxicity.

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Abbreviations

DMPC:

l-α-dimyristoyl phosphatidylcholine

DMPG:

L-α-dimyristoyl phosphatidyl glycerol

DMPA:

l-α-dimyristoyl phosphatidic acid

TLC:

thin-layer chromatography

PBS:

phosphate-buffered saline containing 8 mM Na2HPO4, 1 mM KH2PO4 and the specified amount of KCl(pH 7.4)

Tm :

gel to liquid-crystalline phase transition temperature

DMPG:

l-α-dimyristoyl phosphatidyl glycerol

SUVs:

small unilamellar vesicles

References

  1. Acton EM (1980) N-Alkylation of anthracyclines. In: Crooke ST, Reich SD (eds) Antracyclines: Current status and new developments. Academic Press, New York

    Google Scholar 

  2. Acton EM, Tong GL, Mosher CW, Wolgemuth RL (1984) Intensely potent morpholinyl anthracyclines. J Med Chem 27:638–645

    Google Scholar 

  3. Bachur NR, Gordon SL, Gee MV (1977) Anthracycline antibiotic augmentation of microsomal electron transport and free radical formation. Mol Pharmacol 13: 901–910

    Google Scholar 

  4. Barthelemy-Clavey V, Maurizot JC, Dimicoli JL, Sicard P (1974) Self-association of daunorubicin. FEBS Lett 46: 5–10

    Google Scholar 

  5. Burke TG, Tritton TR (1984) Ligand self-association at the surface of liposomes: a complication during equilibriumbinding studies. Anat Biochem 143: 135–140

    Google Scholar 

  6. Burke TG, Tritton TR (1985 a) Structural basis of anthracycline selectivity for unilamellar phosphatidylcholine vesicles: an equilibrium-binding study. Biochemistry 24: 1768–1776

    Google Scholar 

  7. Burke TG, Tritton TR (1985 b) Location and dynamics of anthracyclines bound to unilamellar phosphatidyl vesicles. Biochemistry 24: 5972–5980

    Google Scholar 

  8. Burke TG, Morin MJ, Sartorelli AC, Lane PE, Tritton TR (1987) Function of the anthracycline amine in membrane binding: Cellular transport and cytotoxicity. Mol Pharmacol 31: 552–556

    Google Scholar 

  9. Calendi E, DiMarco A, Reggiani M, Scarpinato B, Valentini L (1965) On physico-chemical interactions between daunomycin and nucleic acid. Biochim Biophys Acta 103: 25–49

    Google Scholar 

  10. Chaires JB, Dattagupta N, Crothers DM (1982) Self-association of daunomycin. Biochemistry 21:3927–3932

    Google Scholar 

  11. Chang EL, Gaber BP, Sheridan JP (1982) Photon correlation spectroscopy study on the stability of small unilamellar DPPC vesicles. Biophys J 39: 197–201

    Google Scholar 

  12. Dalmark M, Storm HH (1981) A Fickian diffusion transport process with features of transport catalysis. Doxorubicin transport in human red blood cells. J Gen Physiol 78: 349–364

    Google Scholar 

  13. Duarte-Karim M, Ruyscchaert JM, Hildebrand J (1976) Affinity of adriamycin to phospholipids: a possible explanation of cardiac mitochondrial lesions. Biochem Biophys Res Commun 71: 658–663

    Google Scholar 

  14. Gaber BP, Sheridan JP (1982) Kinetic and thermodynamic studies of the fusion of small unilamellar phospholipid vesicles. Biochim Biophys Acta 685: 87–93

    Google Scholar 

  15. Goldman R, Facchinetti T, Bach D, Raz A, Shinitzki M (1978) A differential interaction of daunomycin, adriamycin and their derivatives with human erythrocytes and phospholipid bilayers. Biochim Biophys Acta 512: 254–269

    Google Scholar 

  16. Goodman J, Hochstein P (1977) Generation of free radicals and lipid peroxidation by redox cycling of adriamycin and daunomycin. Biochem Biophys Res Commun 77: 797–803

    Google Scholar 

  17. Goormaghtigh E, Chatelain P, Caspers J, Ruysschaert JM (1980) Evidence of a specific complex between adriamycin and negatively charged phospholipids. Biochim Biophys Acta 597: 1–14

    Google Scholar 

  18. Graham I, Gagne J, Silvius JR (1985) Kinetics and thermodynamics of calcium-induced lateral phase separations in phosphatidic acid containing bilayers. Biochemistry 24: 7123–7131

    Google Scholar 

  19. Henry N, Fantine EO, Bolard J, Garnier-Suillerot A (1985) Interaction of adriamycin with negatively charged model membranes evidence of two types of binding sites. Biochemistry 24: 7085–7092

    Google Scholar 

  20. Kraczmar GS, Tritton TR (1979) The interaction of adriamycin with small unilamellar vesicle liposomes. A fluorescence study. Biochim Biophys Acta 557: 306–319

    Google Scholar 

  21. Kovaouci R, Silvius JR, Graham I, Pezolet M (1985) Calcium-induced lateral phase separations in phosphatidylcholine-phosphatidic acid mixtures. A Ramon spectroscopic study. Biochemistry 24: 7132–7140

    Google Scholar 

  22. Lenaz L, Page JA (1976) Cardiotoxicity of adrimycin and related anthracyclines. Cancer Treat Rev 3: 111–120

    Google Scholar 

  23. Martin SR (1980) Absorption and circular dichroic spectral studies on the self-association of daunorubicin. Biopolymers 19: 713–721

    Google Scholar 

  24. Menozzi M, Valentini L, Vannini E, Arcamone F (1984) Selfassociation of doxorubicin and related compounds in aqueous solutions. J Pharm Sci 73: 766–770

    Google Scholar 

  25. Mosher CW, Wu HY, Fujiwara AN, Acton EM (1982) Enhanced antitumor properties of 3′-(4-morpholinyl) and 3′-(4-methoxy-1-piperidinyl) derivatives of 3′-deaminodaunorubicin. J Med Chem 25: 18–24

    Google Scholar 

  26. Papahadjopoulos D, Hui S, Vail WJ, Poste G (1976a) Studies on membrane fusion: I. Interactions of pure phospholipid membranes and the effects of myristic acid, lysolecithin, proteins and dimethyl sulfoxide. Biochim Biophys Acta 448: 245–264

    Google Scholar 

  27. Papahadiopoulos D, Vail WJ, Pangborn WA, Poste G (1976 b) Studies on membrane fusion: II. Introduction of fusion in pure phospholipid membranes by calcium ions and other divalent metals. Biochim Biophys Acta 448: 265–283

    Google Scholar 

  28. Poste GE, Papahadjopoulas D, Vail WJ (1976) Lipid vesicles as carriers for introducing biologically active materials into cells. Methods Cell Biol 14: 33–71

    Google Scholar 

  29. Rogers KE, Tokes ZA (1984) Novet mode of cytotoxicity obtained by coupling inactive anthracycline to a polymer. Biochem Pharmacol 33: 605–608

    Google Scholar 

  30. Rogers KE, Carr BI, Tokes ZA (1983) Cell surface-mediated cytotoxicity of polymer-bound adriamycin against drug resistant hepatocytes. Cancer Res 43: 2741–2748

    Google Scholar 

  31. Siegfreid JM, Burke TG, Tritton TR (1985) Cellular transport of anthracyclines by passive diffusion. Implications for drug resistance. Biochem Pharmacol 34: 593–598

    Google Scholar 

  32. Sturgeon RJ, Schulman SG (1977) Electronic absorption spectra and protolytic equilibria of doxorubicin direct spectrophotometric determination of microconstants. J Pharm Sci 66: 958–961

    Google Scholar 

  33. Suurkuusk J, Lentz BR, Barenholz Y, Biltonen RL, Thompson TE (1976) A calorimetric and fluorescent probe study of gel-liquid crystalline phase transition in small, single-lamellar dipalmitoylphosphatidylcholine vesicles. Biochemistry 15: 1393–1401

    Google Scholar 

  34. Thayer WS (1977) Adriamycin stimulated superoxide formation in submitochondrial particles. Chem Biol Interact 19: 265–278

    Google Scholar 

  35. Tokes ZA, Rogers KE, Rembaum A (1982) Synthesis of adriamycin-coupled polyglutaraldehyde microspheres and evaluation of their cytostatic activity. Proc Natl Acad Sci USA 79: 2026–2030

    Google Scholar 

  36. Tong GL, Wu HY, Smith TH, Henry DW (1979) Adriamycin analogues: 3. Synthesis of N-alkylated anthracyclines with enhanced efficacy and reduced cardiotoxicity. J Med Chem 22: 912–918

    Google Scholar 

  37. Tritton TR, Yee G (1982) The anticancer agent adriamycin can be actively cytotoxic without entering cells. Science 217: 248–250

    Google Scholar 

  38. Tritton T, Murphree S, Sartorelli A (1978) Adriamycin: a proposal on the specificity of drug action. Biochem Biophys Res Commun 84: 802–808

    Google Scholar 

  39. Wingard LB Jr, Tritton TR, Egler KA (1985) Cell surface effects of adriamycin and corminomycin immobilized on cross-linked polyvinyl alcohol. Cancer Res 45: 3529–3536

    Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology, University of Vermont Medical School, 05405, Burlington, VT, USA

    Thomas R. Tritton

  2. Vermont Regional Cancer Center, University of Vermont Medical School, 05405, Burlington, VT, USA

    Thomas R. Tritton

  3. Department of Pharmacology and Developmental Therapeutics Program, Comprehensive Cancer Center, Yale University School of Medicine, 06510, New Haven, CT, USA

    Thomas G. Burke & Alan C. Sartorelli

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  1. Thomas G. Burke
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  2. Alan C. Sartorelli
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  3. Thomas R. Tritton
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Additional information

This research was supported in part by U. S. Public Health Service Grants CA-02817, CA-44729, and CA-01088 from the National Cancer Institute and by a grant from the American Cancer Society (CH-392).

This research was supported in part by U. S. Public Health Service Grants CA-02817, CA-44729, and CA-01088 from the National Cancer Institute and by a grant from the American Cancer Society (CH-392).

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Burke, T.G., Sartorelli, A.C. & Tritton, T.R. Selectivity of the anthracyclines for negatively charged model membranes: role of the amino group. Cancer Chemother. Pharmacol. 21, 274–280 (1988). https://doi.org/10.1007/BF00264191

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  • DOI: https://doi.org/10.1007/BF00264191

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