Membrane Transport of Antifolates as a Critical Determinant of Drug Cytotoxicity

  • I. David Goldman
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 84)


There are few areas in therapeutics in which membrane transport of pharmacologic agents has been subjected to as intense study as in the treatment of malignant diseases with cytotoxic agents. Unlike the antibacterial or antifungal agents, which may selectively inhibit biochemical processes unique to the bacterial or fungal organism, the agents which comprise the current armamentarium of the cancer chemotherapist produce toxic effects on both tumor and susceptible host tissues. The lack of understanding of the basic biochemical differences between normal and malignant cells require the utilization of subtle techniques, often empirical, to achieve “selective” effects of the agents in an attempt to minimize toxicity to susceptible host tissues while maximizing toxicity to the tumor. The better understood of these techniques usually exploit quantitative rather than qualitative differences in the tumor vs. host cell rates of (a) cellular proliferation, (b) drug activation or inactivation, (c) drug transport across the cell membrane, and (d) drug interaction with target sites within the cell.


Membrane Transport Free Drug Organic Phosphate Ehrlich Ascites Tumor Cell Intracellular Drug 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    BLAKELY, R.L.: The Biochemistry of Folic Acid and Related Pteridines. North Holland, Amsterdam (1969).Google Scholar
  2. 2.
    HAKALA, M.T.: Biochim. Biophys. Acta 102 (1965) 198.PubMedCrossRefGoogle Scholar
  3. 3.
    GOLDMAN, I.D., LICHTENSTEIN, N.S., And OLIVERIO, V.T.: J. Biol. Chem. 243 (.1968) 5007.PubMedGoogle Scholar
  4. 4.
    KESSEL, D., HALL, T., And ROBERTS, D.: Science 150 (1965) 752.PubMedCrossRefGoogle Scholar
  5. 5.
    GOLDMAN, I.D.: Uptake of Drugs and Resistance, Ch. 8, Drug Resistance and Selectivity: Biochemical and Cellular Basis (E. Mihich, ed.). Academic Press. New York (1973).Google Scholar
  6. 6.
    GOLDMAN, I.D.: Mol. Pharmacol. 10 (1974) 257.PubMedGoogle Scholar
  7. 7.
    GOLDMAN, I.D., and FYFE, M.J.: Mol. Pharmacol. 10 (1974) 275.PubMedGoogle Scholar
  8. 8.
    WHITE, J.C., LOFTFIELD, S., AND GOLDMAN, I.D.: Mol. Pharmacol. 11 (.1975) 287.Google Scholar
  9. 9.
    WHITE, J.C., and GOLDMAN, I.D.: Mol. Pharmacol, in press.Google Scholar
  10. 10.
    GOLDMAN, I.D.: Cancer Chemother. Rep. 6 (1975) 51.Google Scholar
  11. 11.
    MARGOLIS, S., PHILIPS, F.S., and STERNBERG, S.S.: Cancer Res. 31 (1971) 2037.PubMedGoogle Scholar
  12. 12.
    CHABNER, B.A., and YOUNG, R.C.: J. Clin. Invest. 52 (1973) 1804.PubMedCrossRefGoogle Scholar
  13. 13.
    SIROTNAK, F.M. and DONSBACH, R.C.: Cancer Res. 33 (1973) 1290.PubMedGoogle Scholar
  14. 14.
    SIROTNAK, F.M., and DONSBACH, R.C.: Cancer Res. 35 (1975) 1737.PubMedGoogle Scholar
  15. 15.
    SIROTNAK, F.M. and DONSBACH, R.C.: Cancer Res. 36 (1976) 1151.PubMedGoogle Scholar
  16. 16.
    WERKHEISER, W.C.: J. Biol. Chem. 236 (1961) 888.Google Scholar
  17. 17.
    WHITE, J.C., Poe, M., and Goldman, I.D.: Unpublished data.Google Scholar
  18. 18.
    JACKSON, R.C., and HARRAP, K.R.: Arch. Biochem. Biophys. 158 (1973) 827.PubMedCrossRefGoogle Scholar
  19. 19.
    ROTHENBERG, S.P., DA COSTA, M., and IQBAL, M.P.: Proc. Am. Assoc. Cancer Res. 17 (1976) 106,Google Scholar
  20. 20.
    GOLDMAN, I.D.; Cancer Chemother. Rep., in press,Google Scholar
  21. 21.
    GOLDMAN, I.D.: Ann. N.Y. Acad. Sci. 186 (1971) 400,Google Scholar
  22. 22.
    GOLDMAN, I.D.: Cancer Chemother. Rep. 6 (1975) 63.Google Scholar
  23. 23.
    RADER, I., NIETHAMMER, C., and HUENNEKENS, F.M,: Biochem. Pharmacol. 23 (1974) 2057.PubMedCrossRefGoogle Scholar
  24. 24.
    SIROTNAK, F.M., and DONSBACH, R.C.: Cancer Res. 32 (1972) 2120.PubMedGoogle Scholar
  25. 25.
    GOLDMAN, I.D.: Proc. Am. Assoc. Cancer Res. 17 (1976) 130.Google Scholar
  26. 26.
    GOLDMAN, I.D.: Biochim. Biophys, Acta 233 (1971) 624.CrossRefGoogle Scholar
  27. 27.
    GOLDMAN, I.D., WHITE, J.C., and BAILEY, B.D,: Unpublished data.Google Scholar
  28. 28.
    GOLDMAN, I.D.: J. Biol. Chem. 244 (1969) 3779.PubMedGoogle Scholar
  29. 29.
    GOLDMAN, I.D., SNOW, R., and WHITE, J.C., Fed. Proc. 34 (1975) 807.Google Scholar
  30. 30.
    GOLDMAN, I.D., GUPTA, V., WHITE, J.C., and LOFTFIELD, S,: Cancer Res. 36 (1976) 276.PubMedGoogle Scholar
  31. 31.
    LASSEN, U.V., NIELSON, A.-M.T., and SIMONSEN, L.O.: J. Membrane Biol. 6 (1971) 269.CrossRefGoogle Scholar
  32. 32.
    Na-Linked Transport of Organic Solutes (E. Heinz, ed.) Springer-Verlag. Heidelberg (1972).Google Scholar
  33. 33.
    JENNETTE, J.C., and GOLDMAN, I.D.: J. Lab. Clin. Med. 86 (1975) 834.PubMedGoogle Scholar
  34. 34.
    SIROTNAK, F.M., and DONSBACH, R.C.: Biochem. Pharmacol. 24 (1975) 156.PubMedCrossRefGoogle Scholar
  35. 35.
    GOLDMAN, I.D.: Proc. Am. Assoc. Cancer Res. 17 (1976) 130.Google Scholar
  36. 36.
    FYFE, M.J., and GOLDMAN, I.D.: J. Biol. Chem. 248 (1973) 5067.PubMedGoogle Scholar
  37. 37.
    ZAGER, R.F., FRISBY, S.A., and OLIVERIO, V.T.: Cancer Res. 33 (1973) 1670.PubMedGoogle Scholar
  38. 38.
    BENDER, R.A., BLEYER, W.A., FRISBY, S.A.: Cancer Res. 35 (1975) 1305.PubMedGoogle Scholar
  39. 39.
    JAFFE, N., FREI, E. III, TRAGGIS, D., and BISHIP, Y.: New Engl. J. Med. 291 (1974) 994.PubMedCrossRefGoogle Scholar
  40. 40.
    FYFE, M.J., LOFTFIELD, S., and GOLDMAN, I.D.: J. Cell. Physiol. 86 (1975) 201.PubMedCrossRefGoogle Scholar
  41. 41.
    FYFE, M.J., GOLDMAN, I.D.: Fed. Proc. 34 (1975) 250.Google Scholar
  42. 42.
    SCHAFER, J.A., and GOLDMAN, I.D.: Fed. Proc. 35 (1976) 605.Google Scholar

Copyright information

© Plenum Press, New York 1977

Authors and Affiliations

  • I. David Goldman
    • 1
  1. 1.Department of MedicineMedical College of VirginiaRichmondUSA

Personalised recommendations