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Biochemical pharmacology of 5,6-dihydro-5-azacytidine (DHAC) and DNA hypomethylation in tumor (L1210)-bearing mice

Summary

Dihydro-5-azacytidine (DHAC) is a hydrolytically stable congener of 5-azacytidine, which retains antileukemic activity against experimental leukemias. The biochemical pharmacology of DHAC was studied in tumor-bearing mice in order to elucidate the mode of action of this drug. We found that after an LD10 dose of DHAC, the plasma peak concentration achieved was 317 μM and was eliminated biexponentially, with a t1/2α of 1.03 h and a t1/2β of 5 h. By 4h, an unidentified metabolite of [3H]DHAC peaked and was eliminated biexponentially, with a t1/2α of 1.06 h and a t1/2β of 10.6 h. [3H]DHACTP was the major anabolite in the L1210/0 cells, and was also eliminated biexponentially, with a t1/2α of 4.3 h and a t1/2β of 12.2 h. An unknown anabolite of [3H]DHAC that eluted 5 min after [3H]DHACTP, between UTP and ATP, peaked at 3 h and could possibly be the deoxy-derivative [3H]DHAdCTP. A tissue distribution study revealed that the liver, L1210/0, and lung accumulate the most radioactivity per gram of wet tissue. Methylation studies showed that an LD10 dose of [3H]DHAC resulted in a 25.06% hypomethylation of DNA in L1210/0 cells and a 46.32% hypomethylation in a deoxycytidine kinase mutant cell line L1210/dCK(-), compared with their respective controls.

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Abbreviations

5-aza-C:

5-azacytidine

DHAC:

5,6-dihydro-5-azacytidine

DHACTP:

dihydro-5-azacytidine 5′-triphosphate

DHAdCTP:

dihydro-5-azacytidine 5′-deoxytriphosphate

LD10 :

lethal dose 10% of animals

UTP:

uridine 5′-triphosphate

ATP:

adenosine 5′-triphosphate

TCA:

trichloroacetic acid

PCA:

perchloric acid

RBC:

red blood cells

i.p.:

intraperitoneally

SAX:

strong anion exchange

SCX:

strong cation exchange

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Author information

Correspondence to Vassilios I. Avramis.

Additional information

Supported by a research grant, CA 38905, from the National Institutes of Health, NCI

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Powell, W.C., Avramis, V.I. Biochemical pharmacology of 5,6-dihydro-5-azacytidine (DHAC) and DNA hypomethylation in tumor (L1210)-bearing mice. Cancer Chemother. Pharmacol. 21, 117–121 (1988). https://doi.org/10.1007/BF00257356

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Keywords

  • Leukemia
  • Mutant Cell
  • Deoxycytidine
  • Respective Control
  • Plasma Peak Concentration