Enhancement of the toxicity and DNA incorporation of arabinosyl-5-azacytosine and 1-beta-D-arabinofuranosylcytosine by cyclopentenyl cytosine.

Abstract

We evaluated the interaction of a biochemically active concentration of cyclopentenyl cytosine (CPE-C), an investigational antimetabolite which inhibits CTP synthetase, on the cytotoxicity of arabinosyl-5-azacytosine (Ara-AC) and 1-beta-D-arabinofuranosylcytosine (Ara-C) in HCT 116 colon carcinoma cells. A 3-h exposure to 0.5 microM CPE-C depleted CTP pools by over 90% and decreased dCTP pools by 57%; the effect on CTP pools persisted for up to 24 h following washout of CPE-C. A 3-h pre-exposure to 0.5 microM CPE-C augmented the growth inhibition resulting from a 24-h exposure to Ara-AC. The combination of 1 microM cytidine and deoxycytidine fully reversed the enhancement associated with CPE-C pretreatment, to a level of growth inhibition expected from either CPE-C or Ara-AC alone. A striking enhancement of toxicity was observed in clonogenic studies with pre-exposure to CPE-C at a nonlethal dose followed by either Ara-AC or Ara-C. CPE-C increased the formation of Ara-AC and Ara-C nucleotides by as much as 3-fold, and this was accompanied by increased incorporation of the arabinosyl nucleotides into methanol-precipitable material. Analysis of purified RNase-treated nucleic acids by cesium sulfate density centrifugation confirmed that a 3-h pre-exposure to CPE-C increased [3H]-Ara-C incorporation into DNA at 4 and 24 h by 2.4- and 2.7-fold, respectively. Thus, these studies indicate that CPE-C can function as a biochemical modulator. Following a brief exposure to a nonlethal concentration, CPE-C is capable of augmenting the cytotoxicity and intracellular metabolism of Ara-AC and Ara-C.

• Authors: J L Grem, C J Allegra
• Journal: Cancer research (Cancer Res) Vol. 50 Issue 22 Pg. 7279-84 (Nov 15 1990) ISSN: 0008-5472 [Print] United States
• PMID: 1699659 (Publication Type: Journal Article)

Chemical References

• Antimetabolites, Antineoplastic
• DNA, Neoplasm
• Deoxycytosine Nucleotides
• Cytarabine
• 2'-deoxycytidine 5'-triphosphate
• fazarabine
• Cytidine Triphosphate
• Azacitidine

Topics

• Antimetabolites, Antineoplastic (administration & dosage, toxicity)
• Azacitidine (metabolism, toxicity)
• Cell Survival (drug effects)
• Colorectal Neoplasms (pathology)
• Cytarabine (metabolism, toxicity)
• Cytidine Triphosphate (metabolism)
• DNA, Neoplasm (metabolism)
• Deoxycytosine Nucleotides (metabolism)
• Humans
• In Vitro Techniques
• Tumor Cells, Cultured (drug effects)