Sequence-dependent interaction of 5-fluorouracil and arabinosyl-5-azacytosine or 1-beta-D-arabinofuranosylcytosine.

Abstract

We studied the cytotoxicity of arabinosyl-5-azacytosine (Ara-AC), a dCyd antagonist which inhibits DNA synthesis, in combination with 5-fluorouracil (FUra) in two human colon cancer cell lines, HCT 116 and SNU-C4. Clonogenic assays done following sequential or concurrent 24-hr exposures to Ara-AC and FUra showed that the sequence Ara-AC followed by FUra resulted in more than additive lethality in the HCT 116 cell lines and additive lethality in the SNU-C4 cells. In contrast, the reverse sequence, FUra followed by Ara-AC, was antagonistic in both cell lines. A similar interaction between FUra and 1-beta-D-arabinofuranosylcytosine (Ara-C) was evident in HCT 116 cells; at concentrations which individually diminished viability by 34 and 62%, respectively, the sequence Ara-C followed by FUra decreased viability by 97%. Pulse-labeling with [3H]dUrd showed profound inhibition of DNA synthesis by the sequence Ara-AC followed by FUra, with over 90% inhibition lasting for up to 48 hr following Ara-AC exposure. When FUra preceded Ara-AC, however, earlier recovery from inhibition of DNA synthesis occurred. FUra pretreatment did not appreciably alter the quantity or distribution of [3H]Ara-AC or [3H]Ara-C nucleotides after a 4- to 6-hr exposure. Pre-exposure to FUra decreased Ara-AC incorporation into DNA by 37 and 73% at 6 hr in HCT 116 and SNU-C4, respectively. FUra pretreatment also inhibited Ara-C incorporation into DNA by over 50% at 6 and 24 hr. The antagonism of Ara-AC and Ara-C cytotoxicity by FUra pretreatment can thus be explained by diminished incorporation of the dCyd analogs into DNA resulting from inhibition of DNA synthesis by FUra-induced dTTP and dCTP depletion. In contrast, when Ara-AC or Ara-C preceded FUra, their incorporation into DNA was not disturbed, and prolonged inhibition of DNA synthesis was observed.

• Authors: J L Grem, C J Allegra
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 42 Issue 2 Pg. 409-18 (Jul 05 1991) ISSN: 0006-2952 [Print] England
• PMID: 1713459 (Publication Type: Journal Article)

Chemical References

• DNA, Neoplasm
• Deoxycytosine Nucleotides
• Nucleic Acids
• Thymine Nucleotides
• Cytarabine
• 2'-deoxycytidine 5'-triphosphate
• Cytidine
• fazarabine
• Azacitidine
• thymidine 5'-triphosphate
• Fluorouracil

Topics

• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Azacitidine (administration & dosage, pharmacology)
• Cell Division (drug effects)
• Cell Line (drug effects)
• Cell Nucleus (drug effects)
• Cell Survival (drug effects)
• Colonic Neoplasms (drug therapy, pathology)
• Cytarabine (administration & dosage, pharmacology)
• Cytidine (antagonists & inhibitors)
• DNA, Neoplasm (biosynthesis)
• Deoxycytosine Nucleotides (metabolism)
• Drug Administration Schedule
• Drug Interactions
• Fluorouracil (administration & dosage, pharmacology)
• Humans
• Nucleic Acids (metabolism)
• Thymine Nucleotides (metabolism)
• Tumor Stem Cell Assay