Cellular metabolism of 1-beta-D-arabinofuranosyl-5-azacytosine and incorporation into DNA and RNA of human lymphoid CEM/0 and CEM/dCk(-) cells.

Cancer Chemotherapy and Pharmacology
V I AvramisR A Mecum

Abstract

1-beta-D-arabinosyl-5-azacytosine (ara-AC) is a relatively new antitumor agent under clinical investigation, which has the 2'-beta arabinosyl configuration found in the tumoricidal drug ara-C and the nitrogen substitution in the 5-position of the pyrimidine ring found in 5-azacytidine (5-aza-C). The present study examined the cellular metabolism and the effect on DNA methylation of ara-AC in human CCRF/CEM cells sensitive and resistant to ara-C. The triphosphate anabolite of the drug, ara-ACTP, was the major anabolite in the CEM cellular extracts, peaking at 50.6 +/- 23 microM 4 h after incubation with IC50 concentrations (0.25 microM) of [3H]ara-AC. The mono- and diphosphate anabolites accumulated 10-fold lower cellular concentrations than ara-ACTP. The nucleoside triphosphate (NTP) pools and, especially, cellular ATP declined significantly by 9 h after the initiation of drug treatment and remained depleted for the 24-h treatment. The drug anabolite was gradually incorporated into both RNA and DNA, peaking in CEM/0 at 3.44 and 0.14 nmol/10(7) cells, respectively. The DNA methylation levels in these cells declined rapidly after treatment with ara-AC, attaining a nadir plateau at 29% of control methylation value. The deoxycytidi...Continue Reading

References

Oct 1, 1979·Journal of Medicinal Chemistry·J A BeislerJ S Driscoll
May 24, 1979·The New England Journal of Medicine·R P Gale
Nov 1, 1984·Proceedings of the National Academy of Sciences of the United States of America·D V SantiC E Garrett

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Citations

Feb 1, 1993·Investigational New Drugs·N Ben-BaruchK H Cowan
Jan 5, 2006·Annals of Hematology·Michael A Morgan, Christoph W M Reuter

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