Cancer Chemotherapy and Pharmacology

, Volume 27, Issue 4, pp 258–262 | Cite as

Saturation of 2′, 2′-difluorodeoxycytidine 5′-triphosphate accumulation by mononuclear cells during a phase I trial of gemcitabine

  • Ralf Grunewald
  • James L. Abbruzzese
  • Peter Tarassoff
  • William Plunkett
Original Articles 2-Difluorodeoxycytidine, Mononuclear Cells, Phase I Trial, Gemcitabine


The plasma and cellular pharmacology of 2′, 2′-difluorodeoxycytidine (dFdC, Gemcitabine) was studied during a phase I trial. The steady-state concentration of dFdC in plasma was directly proportional to the dFdC dose, which ranged between 53 and 1,000 mg/m2 per 30 min. The cellular pharmacokinetics of an active metabolite, dFdC 5′-triphosphate (dFdCTP), were determined in mononuclear cells of 22 patients by anion-exchange highpressure liquid chromatography. The rate of dFdCTP accumulation and the peak cellular concentration were highest at a dose rate of 350 mg/m2 per 30 min, during which steady-state dFdC levels of 15–20 μM were achieved in plasma. A comparison of patients infused with 800 mg/m2 over 60 min with those receiving the same dose over 30 min demonstrated that the dFdC steady-state concentrations were proportional to the dose rate, but that cellular dFdCTP accumulation rates were similar at each dose rate. At the lower dose rate, the AUC for dFdCTP accumulation was 4-fold that observed at the higher dose rate. Consistent with these observations, the accumulation of dFdCTP by mononuclear cells incubated in vitro was maximal at 10–15 μM dFdC. These studies suggest that the ability of mononuclear cells to use dFdC for triphosphate formation is saturable. In the design of future protocols, a dose rate should be considered that produces maximal nucleotide analogue formation, with increased intensity being achieved by prolonging the duration of infusion.


Mononuclear Cell Gemcitabine Triphosphate Dose Rate Accumulation Rate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.





steady-state concentration of ara-C


5′-triphosphate of ara-C


2′, 2′-difluorodeoxycytidine, Gemcitabine


steady-state concentration of dFdC


5′-triphosphate of dFdC


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Abbruzzese JL, Grunewald R, Weeks EA, Gravel D, Adams T, Nowak B, Mineishi S, Tarassoff P, Saterlee W, Raber MN, Plunkett W (1990) A phase I clinical, plasma and cellular pharmacology study of 2′, 2′-difluorodeoxycytidine. J Clin Oncol (in press)Google Scholar
  2. 2.
    Chou T-C, Arlin Z, Clarkson BD, Philips FS (1977) Metabolism of 1-β-d-arabinofuranosylcytosine in human leukemic cells. Cancer Res 37: 3561–3570Google Scholar
  3. 3.
    Estey E, Keating MJ, McCredie KB, Freireich EJ, Plunkett W (1990) Cellular ara-CTP pharmacokinetics, response, and karyotype in newly diagnosed acute myelogenous leukemia. Leukemia 4: 95–99Google Scholar
  4. 4.
    Gandhi V, Plunkett W (1990) Modulatory activity of 2′, 2′-difluorodeoxycytidine on the phosphorylation and cytotoxicity of arabinosyl nucleosides. Cancer Res 50: 3675–3680Google Scholar
  5. 5.
    Grunewald R, Kantarjian H, Keating MJ, Abbruzzese J, Tarasoff P, Plunkett W (1990) Pharmacologically directed design of the dose rate and schedule of 2′, 2′-difluorodeoxycytidine administration in leukemia. Cancer Res 50: 6822–6826Google Scholar
  6. 6.
    Harris AL, Grahame-Smith DG (1979) Variation in sensitivity of DNA synthesis to ara-C in acute myeloid leukemia. Br J Haematol 45: 371–379Google Scholar
  7. 7.
    Heinemann V, Hertel LW, Grindey GB, Plunkett W (1988) Comparison of the cellular pharmacokinetics and toxicity of 2′, 2′-difluorodeoxycytidine and 1-β-d-arabinofuranosylcytosine. Cancer Res 48: 4024–4031Google Scholar
  8. 8.
    Heinemann V, Estey E, Keating MJ, Plunkett W (1989) Patient-specific dose rate of continuous infusion high-dose cytarabine in relapsed acute myelogenous leukemia. J Clin Oncol 7: 622–628Google Scholar
  9. 9.
    Heinemann V, Xu YZ, Chubb S, Sen A, Hertel L, Grindey GB, Plunkett W (1990) Inhibition of ribonucleotide reduction in CCRFCEM cells by 2′, 2′-difluorodeoxycytidine. Mol Pharmacol 38: 556–572Google Scholar
  10. 10.
    Hertel LW, Kroin JS, Misner JW, Tustin JM (1988) Synthesis of 2-deoxy-2,2-difluoro-d-ribose and 2-deoxy-2,2-ribofuranosyl nucleosides. J Org Chem 53: 2406–2409Google Scholar
  11. 11.
    Hertel LW, Boder GB, Kroin JS, Rinzel SM, Poore GA, Todd GC, Grindey GB (1990) Evaluation of the antitumor activity of gemcitabine (2′, 2′-difluoro-2′-deoxycytidine). Cancer Res 50: 4417–4422Google Scholar
  12. 12.
    Huang P, Chubb S, Hertel LW, Plunkett W (1990) Mechanism of action of 2′, 2′-difluorodeoxycytidine triphosphate on DNA synthesis. Proc Am Assoc Cancer Res 31: 426Google Scholar
  13. 13.
    Kantarjian HM, Estey EH, Plunkett W, Keating MJ, Walters RS, Iacoboni S, McCredie KB, Freireich EJ (1986) Phase-I-II clinical and pharmacologic studies of high-dose cytosine arabinoside in refractory leukemia. Am J Med 81: 387–394Google Scholar
  14. 14.
    Muus P, Dreth-Schonk A, Haanen C, Wessels H, Linssen P (1987) In-vitro studies on phosphorylation and dephosphorylation of cytosine arabinoside in human leukemia cells. Leukemia Res 11: 319–325Google Scholar
  15. 15.
    Plunkett W, Iacoboni S, Estey E, Danhauser L, Liliemark JO, Keating MJ (1985) Pharmacologically directed ara-C therapy for refractory leukemia. Semin Oncol 12 [Suppl 3]: 20–30Google Scholar
  16. 16.
    Plunkett W, Liliemark JO, Adams TM, Nowak B, Estey E, Kantarjian H, Keating MJ (1987) Saturation of 1-β-d-arabinofuranosyl-cytosine 5′-triphosphate accumulation in leukemia cells during highdose 1-β-d-arabinofuranosylcytosine therapy. Cancer Res 47: 3005–3011Google Scholar
  17. 17.
    Plunkett W, Liliemark JO, Estey E, Keating MJ (1987) Saturation of ara-CTP accumulation during high-dose ara-C therapy: pharmacologic rationale for intermediate-dose ara-C. Semin Oncol 14: [Suppl 1]: 159–166Google Scholar
  18. 18.
    Plunkett W, Gandhi V, Chubb S, Nowak B, Heinemann V, Mineishi S, Sen A, Hertel LW, Grindey GB (1989) 2′, 2′-Difluorodeoxycytidine metabolism and mechanism of action in human leukemia cells. Nucleosides Nucleotides 8: 775–782Google Scholar
  19. 19.
    Sunkara PS, Snyder RS, Jarvi ET, Farr RA (1988) Antitumor activity of 2′-deoxy-2′, 2′-difluorocytidine, a novel inhibitor of ribonucleotide reductase. Proc Am Assoc Cancer Res 29: 324Google Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • Ralf Grunewald
    • 1
  • James L. Abbruzzese
    • 1
  • Peter Tarassoff
    • 2
  • William Plunkett
    • 1
  1. 1.Department of Medical OncologyThe University of Texas M.D. Anderson Cancer CenterHoustonUSA
  2. 2.Lilly Research LaboratoriesIndianapolisUSA

Personalised recommendations