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Chemical Compound Review

dFdCTP     [[[(2R,3R,5R)-5-(4-amino-2- oxo-pyrimidin-1...

Synonyms: AC1L2XS1, 2,2-DF-Ctp, GTF, 2',2'-Difluorodeoxycytidine 5'-triphosphate
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Disease relevance of dFdCTP


High impact information on dFdCTP

  • Gemcitabine is activated by dCyd kinase (dCK) and interferes, as its triphosphate dFdCTP, with tumor growth through incorporation into DNA [3].
  • Paclitaxel did not affect the pharmacokinetics of gemcitabine, nor did gemcitabine affect the pharmacokinetics of paclitaxel, but paclitaxel increased dFdCTP accumulation [4].
  • The results demonstrated that dFdCyd rapidly accumulated as the 5'-triphosphate dFdCTP in HT-29 cells, which was eliminated slowly in the absence of dFdCyd with a half-life of > 12 h [5].
  • PURPOSE: Phase I clinical and in vitro studies of gemcitabine (2',2'-difluorodeoxycytidine; dFdC) have demonstrated that the accumulation rate of dFdC 5'-triphosphate (dFdCTP) in mononuclear and leukemia cells is saturated when plasma or extracellular dFdC levels exceed 15 to 20 mumol/L [6].
  • We examined the values for elimination kinetics of cellular dFdCTP and found they were dependent on cellular concentration after incubation of CCRF-CEM cells with dFdC and washing into drug-free medium [7].

Biological context of dFdCTP

  • The deamination product 2',2'-difluorodeoxyuridine was the predominant extracellular catabolite at low cellular dFdCTP concentrations, whereas at high dFdCTP concentrations dFdC was the major excretion product [7].
  • In addition, dFdCTP inhibited partially purified dCMP deaminase with a 50% inhibitory concentration of 0.46 mM [7].
  • In contrast, a CHO mutant deficient in deoxycytidine kinase, and thus unable to accumulate dFdCTP, maintained its CTP pools under identical conditions, suggesting that the CTP pool depletion was dependent on dFdC phosphorylation [8].
  • Incorporation of dFdCTP into DNA is most likely the major mechanism by which gemcitabine causes cell death [9].
  • Mean plasma Cmax(gemcitabine) and mean dFdCTP AUC in arm A was 20.8 microM +/- 17.2 microM and 35,079 +/- 18,216 microM*min respectively and in arm B, 41.2 +/- 13.9 microM and 32 249 +/- 11 267 microM*min respectively. dFdCTP saturation was reached in Arm B but not in Arm A [10].

Anatomical context of dFdCTP

  • In all cell lines, CDDP failed to increase dFdCTP accumulation at 4- or 24-h exposure to dFdC; in two cell lines, CDDP even tended to decrease dFdCTP accumulation [11].
  • By treating KB cells with radiolabeled-Gem following HU treatment, we further confirmed that the incorporation of dFdCTP into DNA increased 6-fold over control reactions under these conditions [12].
  • The concentration of the active metabolite of gemcitabine, gemcitabine triphosphate (dFdCTP) in peripheral white blood cells, ranged between 37 and 283 pmol/10(6) cells at the end of infusion on day 1 and 35 and 115 pmol/10(6) cells on day 15 [13].
  • The stability of dFdCTP in intact mononuclear blood cells on ice is strongly limited (half-life approximately 100 min) and after freezing the half-life of the analyte in the cellular lysate is approximately 30 min [14].

Associations of dFdCTP with other chemical compounds


Gene context of dFdCTP

  • In addition, the increased CTP, ATP, and UTP pools in the MDR variants might explain the increased ara-CTP and dFdCTP accumulation [17].
  • In order to determine whether lack of dCK affected the formation of the active triphosphate of the deoxycytidine analog dFdC, dFdCTP accumulation and retention was measured in H9 parental and AZT-resistant cells after exposure to 1 and 10 microM dFdC [18].
  • In Colon 26-G, dCK activity was 1.7-fold decreased; dCDA and DNA polymerase were not changed; and Colon 26-G accumulated 1.5-fold less dFdCTP, 6 hours after a gemcitabine injection, than the parental tumor [3].
  • The apparent Ki values of dFdCTP were 11.2 microM for DNA polymerase alpha and 14.4 microM for polymerase epsilon [15].
  • Initial studies of the mechanism of interaction concentrated on the effect of CDDP on dFdCTP accumulation and DNA strand break formation [11].

Analytical, diagnostic and therapeutic context of dFdCTP


  1. Antagonistic effects of sequential administration of BL1521, a histone deacetylase inhibitor, and gemcitabine to neuroblastoma cells. de Ruijter, A.J., Leen, R., Hoebink, J., Caron, H.N., van Kuilenburg, A.B. Cancer Lett. (2006) [Pubmed]
  2. Differential effects of gemcitabine on ribonucleotide pools of twenty-one solid tumour and leukaemia cell lines. van Moorsel, C.J., Bergman, A.M., Veerman, G., Voorn, D.A., Ruiz van Haperen, V.W., Kroep, J.R., Pinedo, H.M., Peters, G.J. Biochim. Biophys. Acta (2000) [Pubmed]
  3. In vivo induction of resistance to gemcitabine results in increased expression of ribonucleotide reductase subunit M1 as the major determinant. Bergman, A.M., Eijk, P.P., Ruiz van Haperen, V.W., Smid, K., Veerman, G., Hubeek, I., van den Ijssel, P., Ylstra, B., Peters, G.J. Cancer Res. (2005) [Pubmed]
  4. Gemcitabine and paclitaxel: pharmacokinetic and pharmacodynamic interactions in patients with non-small-cell lung cancer. Kroep, J.R., Giaccone, G., Voorn, D.A., Smit, E.F., Beijnen, J.H., Rosing, H., van Moorsel, C.J., van Groeningen, C.J., Postmus, P.E., Pinedo, H.M., Peters, G.J. J. Clin. Oncol. (1999) [Pubmed]
  5. Metabolism of 2',2'-difluoro-2'-deoxycytidine and radiation sensitization of human colon carcinoma cells. Shewach, D.S., Hahn, T.M., Chang, E., Hertel, L.W., Lawrence, T.S. Cancer Res. (1994) [Pubmed]
  6. Gemcitabine in leukemia: a phase I clinical, plasma, and cellular pharmacology study. Grunewald, R., Kantarjian, H., Du, M., Faucher, K., Tarassoff, P., Plunkett, W. J. Clin. Oncol. (1992) [Pubmed]
  7. Cellular elimination of 2',2'-difluorodeoxycytidine 5'-triphosphate: a mechanism of self-potentiation. Heinemann, V., Xu, Y.Z., Chubb, S., Sen, A., Hertel, L.W., Grindey, G.B., Plunkett, W. Cancer Res. (1992) [Pubmed]
  8. Gemcitabine: a modulator of intracellular nucleotide and deoxynucleotide metabolism. Heinemann, V., Schulz, L., Issels, R.D., Plunkett, W. Semin. Oncol. (1995) [Pubmed]
  9. Gemcitabine: metabolism, mechanisms of action, and self-potentiation. Plunkett, W., Huang, P., Xu, Y.Z., Heinemann, V., Grunewald, R., Gandhi, V. Semin. Oncol. (1995) [Pubmed]
  10. A multicentre randomised phase II study of carboplatin in combination with gemcitabine at standard rate or fixed dose rate infusion in patients with advanced stage non-small-cell lung cancer. Soo, R.A., Wang, L.Z., Tham, L.S., Yong, W.P., Boyer, M., Lim, H.L., Lee, H.S., Millward, M., Liang, S., Beale, P., Lee, S.C., Goh, B.C. Ann. Oncol. (2006) [Pubmed]
  11. Synergistic interaction between cisplatin and gemcitabine in vitro. Bergman, A.M., Ruiz van Haperen, V.W., Veerman, G., Kuiper, C.M., Peters, G.J. Clin. Cancer Res. (1996) [Pubmed]
  12. Time and sequence dependence of hydroxyurea in combination with gemcitabine in human KB cells. Zhou, B., Mi, S., Mo, X., Shih, J., Tsai, J., Hu, E., Hsu, M., Kay, K., Yen, Y. Anticancer Res. (2002) [Pubmed]
  13. No evidence of gemcitabine accumulation during weekly administration. de Lange, S.M., van der Born, K., Kroep, J.R., Jensen, H.A., Pfeiffer, P., Cleverly, A., van Groeningen, C.J., Peters, G.J. Eur. J. Clin. Pharmacol. (2005) [Pubmed]
  14. Isocratic ion-exchange chromatographic assay for the nucleotide gemcitabine triphosphate in human white blood cells. Sparidans, R.W., Crul, M., Schellens, J.H., Beijnen, J.H. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. (2002) [Pubmed]
  15. Action of 2',2'-difluorodeoxycytidine on DNA synthesis. Huang, P., Chubb, S., Hertel, L.W., Grindey, G.B., Plunkett, W. Cancer Res. (1991) [Pubmed]
  16. 2',2'-Difluoro-deoxycytidine (gemcitabine) incorporation into RNA and DNA of tumour cell lines. Ruiz van Haperen, V.W., Veerman, G., Vermorken, J.B., Peters, G.J. Biochem. Pharmacol. (1993) [Pubmed]
  17. Collateral sensitivity to gemcitabine (2',2'-difluorodeoxycytidine) and cytosine arabinoside of daunorubicin- and VM-26-resistant variants of human small cell lung cancer cell lines. Bergman, A.M., Munch-Petersen, B., Jensen, P.B., Sehested, M., Veerman, G., Voorn, D.A., Smid, K., Pinedo, H.M., Peters, G.J. Biochem. Pharmacol. (2001) [Pubmed]
  18. 3'-Azido-2',3'-dideoxythymidine induced deficiency of thymidine kinases 1, 2 and deoxycytidine kinase in H9 T-lymphoid cells. Gröschel, B., Kaufmann, A., Höver, G., Cinatl, J., Doerr, H.W., Noordhuis, P., Loves, W.J., Peters, G.J., Cinatl, J. Biochem. Pharmacol. (2002) [Pubmed]
  19. Tumor uptake and elimination of 2',2'-difluoro-2'-deoxycytidine (gemcitabine) after deoxycytidine kinase gene transfer: correlation with in vivo tumor response. Blackstock, A.W., Lightfoot, H., Case, L.D., Tepper, J.E., Mukherji, S.K., Mitchell, B.S., Swarts, S.G., Hess, S.M. Clin. Cancer Res. (2001) [Pubmed]
  20. A new, simple method for quantifying gemcitabine triphosphate in cancer cells using isocratic high-performance liquid chromatography. Nishi, R., Yamauchi, T., Ueda, T. Cancer Sci. (2006) [Pubmed]
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