Investigational New Drugs

, Volume 1, Issue 3, pp 243–248 | Cite as

Effect of 2,3-dihydro-1H-imidazo [1,2-b]pyrazole (IMPY) on the metabolism of human red cells

  • Arthur L. SagoneJr.
  • James A. Neidhart
  • Rose Marie Husney


2,3 dihydro-IH-imidazo (1,2-b) pyrazole (IMPY) is a potential chemotherapeutic agent known to inhibit cellular DNA synthesis by blocking ribonucleotide reductase. During Phase I clinical studies with IMPY, patients developed a dose dependent hemolytic anemia possibly secondary to oxidant damage to the RBC. We therefore studied the effect of IMPY on the metabolism of human RBC's in vitro. IMPY, in clinically achievable concentrations, stimulated the hexose monophosphate shunt (HMPS) pathway of RBC's. This was associated with the generation of reactive oxygen species as demonstrated by the glutathione (GSH) instability and enhanced formate oxidation of RBC's incubated with the drug. In addition, the GSH concentration of the red cells of a patient fell during a continuous infusion of IMPY. These effects of IMPY on red cell metabolism in vitro and in vivo are similar to those of drugs known to cause oxidative damage to this cell. The capacity of IMPY to act as an oxidant could explain the hemolytic anemia seen in patients receiving this drug.

Key words

red cells IMPY oxidation HMPS glutathione 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Beutler E, Duron C, Kelly BM: Improved method for the determination of blood glutathione. J Lab Clin Med 61: 882–888, 1963Google Scholar
  2. 2.
    Beutler E: The glutathione instability of drug-sensitive red cells. A new method for the in vitro detection of drug sensitivity. J Lab Clin Med 49:84–95, 1957Google Scholar
  3. 3.
    Brockman RW, Shaddix SC, Carpenter JW, DuBois NF, Struck RF: Studies on the mechanism of 2,3 dihydro-H-pyrazolo (2,3-a) imidazole (NSC 51143). Proc Am Assoc Cancer Res 19:21, 1978Google Scholar
  4. 4.
    Cohen G, Hochstein P: Glutathione peroxidase: The primary agent for the elimination of hydrogen peroxide in erythrocytes. Biochem 2:1420, 1963Google Scholar
  5. 5.
    Cory JG, Fleischer AE: Mode of inhibition of tumor cell ribonucleotide reductase by 2,3 dihydro-1H-pyrazolo (2,3-a) imidazole (NSC 51143). Cancer Res 40:3891–3894, 1980Google Scholar
  6. 6.
    Flanagan CL, Schrier Carson P, Alving A: The hemolytic effect of primaquine VIII. The effect of drug administration on parameters of primaquine sensitivity. J Lab Clin Med 51:600–608, 1958Google Scholar
  7. 7.
    Henderson CA, Metz EN, Balcerzak SP, Sagone AL Jr: Adriamycin and daunomycin generate reactive oxygen compounds in erythrocytes. Blood 52:878–885, 1978Google Scholar
  8. 8.
    Jacob HS, Jandl JH: Effects of sulfhydryl inhibition on red blood cells III Glutathione in the regulation of the hexose monophosphate shunt in erythrocytes. J Biol Chem 241: 4243–249, 1966Google Scholar
  9. 9.
    Metz EN, Balcerzak SP, Sagone AL Jr: Mechanisms of methylene blue stimulation of the hexose monophosphate shunt in erythrocytes. J Clin Invest 58:797–802, 1976Google Scholar
  10. 10.
    Neidhart JA, Staubas AE, Young D, King GW, Malspeis L: Clinical toxic effects of 2,3 dihydro-1H-imidazole (1,2-b) pyrazole (IMPY) with relevant pharmacokinetic parameters. Cancer Treat Rep 64:251–255, 1980Google Scholar
  11. 11.
    Sagone AL Jr, Metz EN, Balcerzak SP: Effect of inorganic phosphate on erythrocyte pentose phosphate pathway activity. Biochim Biophys Acta 261:1–8, 1972Google Scholar
  12. 12.
    Sagone AL Jr, Balcerzak SP, Metz EN: The response of red cell hexose monophosphate shunt after sulfhydrul inhibition. Blood 45:49–54, 1975Google Scholar
  13. 13.
    Sagone AL Jr, Burton GM: The effect of BCNU and Adriamycin on normal and G6PD deficient erythrocytes. Am J Hemat 7:79–106, 1979Google Scholar
  14. 14.
    Sagone AL Jr, Balcerzak SP: Smoking as a cause of erythrocytosis. Ann Intern Med 82:512–515, 1975Google Scholar
  15. 15.
    Sagone AL Jr, Decker MA, Wells RM, Democko C: A new method for the detection of hydroxyl radical production by phagocytic cells. Biochim Biophys Acta 628:90–97, 1980Google Scholar
  16. 16.
    Schrier SL, Kellermeyer R, Carson P, Ickes C, Alving A: The hemolytic effect of Primaquine IX. Enzymatic abnormalities in primaquine-sensitive erythrocytes. J Lab Clin Med 52:109–117, 1958Google Scholar
  17. 17.
    Szeinberg A, Marks P: Substrates stimulating glucose catabolism by oxidative reactions on the pentose phosphate in human erythrocytes. J Clin Invest 40:914–924, 1961Google Scholar
  18. 18.
    Yap B, Murphy WK, Burgess MA, Valdivieso M, Bodex GP: Phase I clinical evaluation of 2,3 dihydro-1h-imidazo (1,2-b) pyrazole. Cancer Treat Rep 63:1849–1851, 1979Google Scholar

Copyright information

© Martinus Nijhoff Publishers 1983

Authors and Affiliations

  • Arthur L. SagoneJr.
    • 1
  • James A. Neidhart
    • 1
  • Rose Marie Husney
    • 1
  1. 1.Department of MedicineOhio State UniversityColumbusUSA

Personalised recommendations