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Basic Sciences

Dose- and Schedule-dependent Activation and Drug Synergism between Thymidine and 5-Aza-2′-Deoxycytidine in a Human Promyelocytic Leukemia Cell Line

Steven Grant, Frank Rauscher III, Judy Margolin and Ed Cadman
Steven Grant
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Frank Rauscher
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Judy Margolin
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Ed Cadman
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DOI:  Published February 1982
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Abstract

The ability of thymidine (dThd) to enhance the metabolism and cytotoxicity of subsequently administered 5-aza-2′-deoxycytidine (5-aza-dCyd) was studied in L1210 cells and in the human promyelocytic leukemic cell line, HL-60. Exposure of L1210 cells to 0.1 mm dThd for 5 hr resulted in an increase in the total intracellular and acid-precipitable accumulation of 5-aza-dCyd. Higher dThd concentrations and longer exposure intervals resulted in smaller increments in 5-aza-dCyd accumulation. In contrast, in HL-60 cells, a 24-hr exposure to 1 mm dThd resulted in the greatest intracellular accumulation of 5-aza-dCyd, 3.3 times more accumulation than in control cells. There was also a 4-fold increase in the acid-precipitable accumulation and nearly a 3-fold increase in DNA incorporation of 5-aza-dCyd in HL-60 cells exposed to the same dThd schedule. High-pressure liquid chromatographic analysis demonstrated a greater than 3-fold increase in the intracellular amounts of 5-aza-dCyd metabolites eluting in the triphosphate region in these human cells under identical conditions. Shorter dThd incubation exposure intervals (6 hr) and lower dThd concentration (0.1 mm) produced smaller increments in these studies.

Both growth inhibition and clonogenic assays of HL-60 cells demonstrated a dose- and schedule sequence-dependent synergism between dThd and 5-aza-dCyd.

Footnotes

  • ↵1 This work was supported in part by Grants CA-24187, CA-09200, CA-27130, and CA-13696 from the National Cancer Institute; Grant CH-145 from the American Cancer Society; and the Cele Butwin Foundation for Cancer Research. Presented in part at the American Federation of Clinical Research, San Francisco, 1981.

  • ↵2 Recipient of a Pharmaceutical Manufacturers Research Starter Grant. Fellow of the Leukemia Society of America. To whom requests for reprints should be addressed.

  • ↵3 Faculty Research Awardee from the American Cancer Society.

  • Received June 19, 1981.
  • Accepted November 5, 1981.
  • ©1982 American Association for Cancer Research.
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February 1982
Volume 42, Issue 2
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Dose- and Schedule-dependent Activation and Drug Synergism between Thymidine and 5-Aza-2′-Deoxycytidine in a Human Promyelocytic Leukemia Cell Line
Steven Grant, Frank Rauscher III, Judy Margolin and Ed Cadman
Cancer Res February 1 1982 (42) (2) 519-524;

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Dose- and Schedule-dependent Activation and Drug Synergism between Thymidine and 5-Aza-2′-Deoxycytidine in a Human Promyelocytic Leukemia Cell Line
Steven Grant, Frank Rauscher III, Judy Margolin and Ed Cadman
Cancer Res February 1 1982 (42) (2) 519-524;
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