Skip to main content
SpringerLink
Log in

Deoxypyrimidine-induced inhibition of the cytokinetic effects of 1-β-d-arabinofuranosyluracil

  • Original Articles
  • Ara-U, Ara-C, Biochemical Modulation
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Summary

Ara-U-induced S-phase accumulation and the interaction between high concentrations of ara-U (HiCAU) and ara-C were investigated in L1210 leukemia cells in vitro. Treatment of exponentially growing L1210 murine leukemia cells with ara-U (200–1000 μm) for 48 h caused a dose-dependent accumulation of cells in the S-phase. The extent of this ara-U-induced S-phase accumulation correlated with ara-U incorporation into DNA and with increases of up to 172% and 464% in the specific activities of deoxycytidine kinase and thymidine kinase, respectively, over control values. Metabolism of 1 μm ara-C following the exposure of cells to ara-U (1mm) resulted in 4.5 pmol ara-C DNA/mg protein vs 2.1 pmol/mg protein in control cells. Although 48-h exposure of cells to 200 and 400 μm ara-U is not cytotoxic, it enhances the cytotoxicity of ara-C (10–100 μm) 4- to 10-fold. Ara-U-induced S-phase accumulation is inhibited by deoxypyrimidine nucleosides but not by pyrimidine or deoxypurine nucleosides. Some of the ara-U and ara-C concentrations used in this study are achievable in clinical practice, and ara-U/ara-C interactions may explain in part the unique therapeutic utility of high-dose ara-C.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

ara-C:

1-β-d-arabinofuranosylcytosine

ara-U:

1-β-d-arabinofuranosyluracil

ara-CTP:

1-β-d-arabinofuranosylcytidine triphosphate

HiDAC:

high-dose ara-C

HiCAU:

high concentrations of ara-U

dCTP:

deoxycytidine triphosphate

HiDAU:

high-dose ara-U

FiTC:

Fluoroisothiocyanate

dUDP:

deoxyuridine diphosphate

dUTP:

deoxyuridine triphosphate

dTTP:

thymidine triphosphate

BrdUrd:

bromodeoxyuridine

dCyd kinase:

deoxycytidine kinase

References

  1. Caminier GW, Smith CG (1965) Studies of the enzymatic deamination of cytosine arabinoside. Biochem Pharmacol 14: 1405

    Google Scholar 

  2. Capizzi RL, Powell BL (1987) Sequential high dose ara-C and asparaginase versus high dose ara-C alone in the treatment of patients with relapsed and refractory acute leukemias. Semin Oncol 14 [Suppl 1]: 40

    Google Scholar 

  3. Capizzi RL, Yang J-L, Cheng E, Bjornson D, Sahasrabudhe D, Tan R-S, Cheng Y-C (1983) Alteration of the pharmacokinetics of high dose ara-C by its metabolite high ara-U in patients with acute leukemia. J Clin Oncol 1: 763

    Google Scholar 

  4. Capizzi RL, Yang J-L, Rathmell JP, White JC, Cheng E, Cheng Y-C, Kute T (1985) Dose-related pharmacologic effects of high dose ara-C and its self-potentiation. Semin Oncol 12 [Suppl 3]: 65

    Google Scholar 

  5. Caradonna SJ, Cheng Y-C (1980) The role of deoxyuridine triphosphate nucleotidohydrolase, uracil-DNA glycosylase, and DNA polymerase α in the metabolism of FUdR in human tumor cells. Mol Pharmacol 18: 513

    Google Scholar 

  6. Caradonna SJ, Cheng YC (1980) Uracil DNA-glycosylase. Purification and properties of this enzyme isolated from blast cells of acute myelocytic leukemia patients. J Biol Chem 255: 2293

    Google Scholar 

  7. Chandrasekaran B, Capizzi RL, Thomas MJ (1986) Ara-U metabolism in murine and human leukemias (abstract). Proc Am Assoc Cancer Res 27: 304

    Google Scholar 

  8. Chandrasekaran B, Capizzi RL, Kute TE, Morgan T, Dimling J (1989) Modulation of the metabolism and pharmacokinetics of 1-β-d-arabinofuranosylcytosine by 1-β-d-arabinofuranosyluracil in leukemic mice. Cancer Res 49: 3259

    Google Scholar 

  9. Cheng Y-C, Prusoff WH (1974) A new rapid assay for measuring deoxycytidylate- and deoxythymidylate-kinase activities. Anal Biochem 60: 545

    Google Scholar 

  10. Cheng Y-C, Domin B, Lee L-S (1977) Human deoxycytidine kinase: purification and characterization of the cytoplasmic and mitochondrial isozymes derived from blast cells of acute myelocytic leukemia patients. Biochim Biophys Acta 481: 481

    Google Scholar 

  11. Chiba P, Tihan T, Eher R, Koller U, Wallner C, Gobl R, Linkesch W (1989) Effect of cell growth and cell differentiation on 1-β-d-arabinofuranosylcytosine metabolism in myeloid cells. Br J Haematol 71: 451

    Google Scholar 

  12. Dolbeare F, Beisker W, Pallavicini MG, Vanderlaan M, Gray JW (1985) Cytochemistry for bromodeoxyuridine/DNA analysis. Cytometry 6: 521

    Google Scholar 

  13. Domena JD, Mosbaugh DW (1985) Purification of nuclear and mitochondrial uracil-DNA glycosylase from rat liver. Identification of two subcellular forms. Biochemistry 24: 7320

    Google Scholar 

  14. Fietkau R, Friede H, Maurer-Schultze B (1984) Cell kinetic studies of the cytostatic cytocidal effect of 1-β-d-arabinofuranosylcytosine on the L1210 ascites tumor. Cancer Res 44: 1105

    Google Scholar 

  15. Ho DHW, Frei E (1971) Clinical pharmacology of 1-β-d-arabino-furanosylcytosine. Clin Pharmacol Ther 12: 944

    Google Scholar 

  16. Karon M, Shirakawa S (1969) The locus of action of 1-β-d-arabinofuranosylcytosine in the cell cycle. Cancer Res 29: 687

    Google Scholar 

  17. Kinahan JJ, Kowal EP, Grindey GB (1981) Biochemical and antitumor effects of the combination of thymidine and 1-β-d-arabinofuranosylcytosine against leukemia L1210. Cancer Res 41: 445

    Google Scholar 

  18. Koistinen P, Ferola E, Vilpo JA (1986) Uracil-DNA glycosylase activity in chronic lymphoproliferative disorders. Leuk Res 10: 1307

    Google Scholar 

  19. Koistinen P, Ferola E, Vilpo JA (1987) Uracil-DNA glycosylase activity in human acute leukemia. Leuk Res 11: 557

    Google Scholar 

  20. Kufe DW, Major PP, Egan ER, Beardsley P (1980) Incorporation of ara-C into L1210 DNA as a correlate of cytotoxicity. J Biol Chem 2355: 8997

    Google Scholar 

  21. Lampkin BC, Nagao T, Mauer AM (1971) Synchronization and recruitment in acute leukemia. J Clin Invest 50: 2204

    Google Scholar 

  22. Makino F, Munakata N (1979) Excision of uracil from bromodeoxyuridine-substituted and UV-irradiated DNA in cultured mouse lymphoma cells. Int J Radiat Biol 36: 349

    Google Scholar 

  23. Muller WEG, Zahn RK (1979) Metabolism of 1-β-d-arabinofuranosyluracil in mouse L5178Y cells. Cancer Res 39: 1102

    Google Scholar 

  24. Rudnick SA, Cadman EC, Capizzi RL, Skeel RT, Bertino JR, McIntosh S (1979) High dose cytosine arabinoside (HDARAC) in refractory acute leukemia. Cancer 44: 1189

    Google Scholar 

  25. Skipper HE, Schabel FM Jr, Wilcox WS (1967) Experimental evaluation of potential anticancer agents: XXI. Scheduling of arabinosylcytosine to take advantage of its S-phase specificity against leukemia cells. Cancer Chemother Rep 51: 125

    Google Scholar 

  26. Strauss BS (1985) Cellular aspects of DNA repair. Adv Cancer Res 45: 45

    Google Scholar 

  27. Townsend AJ, Cheng Y-C (1987) Sequence-specific effects of ara-5-aza-CTP and ara-CTP on DNA synthesis by purified human DNA polymerases in vitro: visualization of chain elongation on a defined template. Mol Pharmacol 32: 330

    Google Scholar 

  28. Vilpo JA (1988) The DNA-repair enzyme uracil-DNA glycosylase in the human hematopoietic system. Mutat Res 193: 207

    Google Scholar 

  29. Walsh CT, Craig RT, Agarwal RP (1980) Increased activation of 1-β-d-arabinofuranosylcytosine by hydroxyurea in L1210 cells. Cancer Res 40: 3286

    Google Scholar 

  30. Wan SH, Hoffman DH, Azarnoff DL (1974) Pharmacokinetics of 1-β-d-arabinofuranosylcytosine in humans. Cancer Res 34: 392

    Google Scholar 

  31. White JC, Rathmell JP, Capizzi RL (1987) Membrane transport influences the rate of accumulation of cytosine arabinoside in human leukemia cells. J Clin Invest 79: 380

    Google Scholar 

  32. Yang J-L, Cheng EH, Capizzi RL, Cheng Y-C, Kute T (1985) Effect of uracil arabinoside on metabolism and cytotoxicity of cytosine arabinoside in L5178Y murine leukemia. J Clin Invest 75: 141

    Google Scholar 

  33. Young RSK, Fischer GA (1968) The action of arabinosylcytosine on synchronously growing populations of mammalian cells. Biochem Biophys Res Commun 32: 23

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Comprehensive Cancer Center of Wake Forest University Winston-Salem, 27103, NC, USA

    Bangaru Chandrasekaran, Timothy E. Kute & Robert L. Capizzi

Authors
  1. Bangaru Chandrasekaran
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Timothy E. Kute
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert L. Capizzi
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Supported in part by grant CH-35H from the American Cancer Society, by Public Health Service grant CA-12197 from the National Cancer Institute, National Institutes of Health, and by the Gaston Cancer Society

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chandrasekaran, B., Kute, T.E. & Capizzi, R.L. Deoxypyrimidine-induced inhibition of the cytokinetic effects of 1-β-d-arabinofuranosyluracil. Cancer Chemother. Pharmacol. 29, 455–460 (1992). https://doi.org/10.1007/BF00684847

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00684847

Keywords

Search

Navigation