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

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.

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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

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Author information

Correspondence to Robert L. Capizzi.

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

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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

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Keywords

  • Pyrimidine
  • Nucleoside
  • Deoxycytidine
  • Thymidine Kinase
  • Therapeutic Utility