Enhancement of the Toxicity and DNA Incorporation of Arabinosyl-5-azacytosine and 1-β-D-Arabinofuranosylcytosine by Cyclopentenyl Cytosine

Jean L. Grem, Carmen J. Allegra

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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-α-D-arabmofuranosylcytosine (Ara-C) in HCT 116 colon carcinoma cells. A 3-h exposure to 0.5 mm 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 µm CPE-C augmented the growth inhibition resulting from a 24-h exposure to Ara-AC. The combination of 1 mm 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.

Original languageEnglish (US)
Pages (from-to)7279-7284
Number of pages6
JournalCancer Research
Volume50
Issue number22
StatePublished - Nov 15 1990

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cyclopentenyl cytosine
fazarabine
Cytarabine
DNA
Cytidine Triphosphate
CTP synthetase
Nucleotides
Antimetabolites
Cytidine
Deoxycytidine

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Enhancement of the Toxicity and DNA Incorporation of Arabinosyl-5-azacytosine and 1-β-D-Arabinofuranosylcytosine by Cyclopentenyl Cytosine. / Grem, Jean L.; Allegra, Carmen J.

In: Cancer Research, Vol. 50, No. 22, 15.11.1990, p. 7279-7284.

Research output: Contribution to journalArticle

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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-α-D-arabmofuranosylcytosine (Ara-C) in HCT 116 colon carcinoma cells. A 3-h exposure to 0.5 mm 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 µm CPE-C augmented the growth inhibition resulting from a 24-h exposure to Ara-AC. The combination of 1 mm 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.",
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