Molecular and chemical neuropathology

, Volume 21, Issue 2–3, pp 111–127 | Cite as

Rationales for cancer chemotherapy with PDMP, a specific inhibitor of glucosylceramide synthase

  • Norman S. Radin


A proposed weak point in cancer cells is their need to synthesize novel or rare glucosphingolipids. It is further proposed that cancer patients be treated with a drug that slows the synthesis of glucosylceramide, the precursor of a large family of glucosphingolipids. Experimental data are furnished for chemotherapeutic and biochemical effects of PDMP, an analog of glucosylceramide and its precursor, ceramide. Promising results were obtained in the treatment of mice carrying Ehrlich ascites carcinoma cells and rats carrying C6 glioma cells. PDMP was found to be oxidized by cytochrome P-450, but this process could be blocked in vivo with piperonyl butoxide or cimetidine. A high level of blood glucose was found to elevate the size of rat kidneys and their content of UDP-glucose and its product, glucosylceramide. The excessive growth could be blocked by PDMP, which competes with UDP-glc for binding to glucosylceramide synthase. It is suggested that cancer patients be maintained at a low glucose level in order to slow the synthesis of glucosylceramide by tumor cells. Metabolic changes produced by PDMP in cultured cells, besides a rapid deletion of glucosphingolipids, were accumulation of the precursors (ceramide and sphingosine), loss of protein kinase C, and accumulation of diacylglycerol. It is suggested that many of the cellular changes produced by PDMP, such as loss of cell binding, are owing to existence of glucosylceramide-based “islands” floating in the outer cell surface; the islands may contain growth factor receptors and adhesion factors. An inhibitor that blocks sphingolipid synthesis, such as cycloserine, may prove to be a useful adjuvant for therapy with PDMP.

Index Entries

Chemotherapy glucosphingolipids ceramide GlcCer synthase PDMP 1-phenyl-2-decanoylamino-3-morpholino-1-propanol sphingosine gliomas 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Barbour S., Edidin M., Felding-Habermann B., Taylor-Norton J., Radin N. S., and Fenderson B. A. (1992).J. Cell. Physiol. 150, 610–619.CrossRefGoogle Scholar
  2. Byrne M. C., Farooq M., Sbaschnig-Agler M., Norton W. T., and Ledeen R. W. (1988).Brain Res. 461, 87–97.CrossRefGoogle Scholar
  3. Felding-Habermann B., Igarashi Y., Fenderson B. A., Park L. S., Radin N. S., Inokuchi J., Strassmann G., Handa K., and Hakomori S. (1990).Biochemistry 29, 6314–6322.CrossRefGoogle Scholar
  4. Fenderson B. A., Radin N., and Andrews P. W. (1993).Eur. Urol. 23 30–37.CrossRefGoogle Scholar
  5. Hakomori S. (1991).Cancer Cells 3, 461–470.PubMedGoogle Scholar
  6. Holmes E. H., Hakomori S., and Ostrander G. K. (1987).J. Biol. Chem. 262, 15649–15658.PubMedGoogle Scholar
  7. Hoon D. S. B., Kaback M. M., Lim-Steele J., Tsuchida T., Morton D. L., and Irie R. F. (1992).Biochem. Int. 27, 343–352.PubMedGoogle Scholar
  8. Inokuchi J., Mason I., and Radin N. S. (1987).Cancer Lett. 38, 23–30.CrossRefGoogle Scholar
  9. Inokuchi J., Momosaki K., Shimeno H., Nagamatsu A., and Radin N. S. (1989)J. Cell. Physiol. 141, 573–583.CrossRefGoogle Scholar
  10. Inokuchi J. and Radin N. S. (1987).J. Lipid Res. 28, 565–571.PubMedGoogle Scholar
  11. Kojima N. and Hakomori S. (1991).J. Biol. Chem. 266, 17552–17558.PubMedGoogle Scholar
  12. Metz R. J. and Radin N. S. (1982).J. Biol. Chem. 257, 12901–12907.PubMedGoogle Scholar
  13. Radin N. S., Brenkert A., Arora R. C., Sellinger O. Z., and Flangas A. L. (1972)Brain Res. 39, 163–169.CrossRefGoogle Scholar
  14. Radin N. S., and Inokuchi J. (1988).Biochem. Pharmacol. 37, 2879–2886.CrossRefGoogle Scholar
  15. Radin N. S., Shayman J. A., and Inokuchi J. (1993) Metabolic effects of inhibiting glucosylceramide synthesis with PDMP and other substances, inAdvances in Lipid Research; Sphingolipids in Signaling, Part B, vol. 26, (Bell R. M., Hannun Y. A., and Merrill A. H., eds.), pp. 183–213, Academic, San Diego.Google Scholar
  16. Rosenwald A. G., Machamer C. E., and Pagano R. E. (1992).Biochemistry 31, 3581–3590.CrossRefGoogle Scholar
  17. Shayman J. A., Deshmukh G., Mahdiyoun S., Thomas T. P., Wu D., Barcelon F. S., and Radin N. S. (1991).J. Biol. Chem. 266, 22968–22974.PubMedGoogle Scholar
  18. Shayman J. A., Mahdiyoun S., Deshmukh G., Barcelon F., Inokuchi J., and Radin N. S. (1990).J. Biol. Chem. 265, 12135–12138.PubMedGoogle Scholar
  19. Shukla A. and Radin N. S. (1991).J. Lipid Res. 32, 713–722.PubMedGoogle Scholar
  20. Shukla G., Shukla A., Inokuchi J., and Radin N. S. (1991).Biochim. Biophys. Acta 1083, 101–108.CrossRefGoogle Scholar
  21. Wachs H. (1947).Science 105, 530, 531.CrossRefGoogle Scholar
  22. Watkins P. B. (1990).Semin. Liver Dis. 10, 235–250.CrossRefGoogle Scholar
  23. Vunnam R. R. and Radin N. S. (1980).Chem. Phys. Lipids 26, 265–278.CrossRefGoogle Scholar
  24. Zador I. Z., Deshmukh G. D., Kunkel R., Johnson K., Radin N. S., and Shayman J. A. (1993).J. Clin. Invest. 91, 797–803.CrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 1994

Authors and Affiliations

  • Norman S. Radin
    • 1
    • 2
  1. 1.Nephrology DivisionUniversity of Michigan Medical CenterAnn Arbor
  2. 2.Mental Health Research InstituteUniversity of MichiganAnn Arbor

Personalised recommendations