Relationship between surviving clonogenic crypt fraction and animal lethality after cytosine arabinoside (Ara-C) exposure

M. G. Pallavicini, C. R. Ng, Joe Gray

Research output: Contribution to journalArticle

Abstract

We have measured animal morbidity and the fraction of clonogenic crypt cells following administration of several doses of Ara-C as an infusion over a 24 h period. A nonlinear relationship between reduction in crypt cell survival and Ara-C induced animal lethality was observed, indicating that factors other than crypt cell toxicity contribute to lethality in conventionally-maintained mice. A dose of 100 mg/kg Ara-C reduced the fraction of surviving clonogenic crypt cells to 7 × 10-3 without animal lethality. However, 300 mg/kg reduced crypt clonogenic cell survival only to 4× 10-3 while killing 50 percent of the animals. Maintenance of the animals on acid water before and after Ara-C treatment reduced animal lethality substantially. The magnitude of the reduction of clonogenic crypt cells was incompatible with S-phase specific toxicity as the only cytotoxic mechanism, and suggested that cell recruitment and crypt cell kill due to unbalanced growth are also operative during Ara-C infusion. In addition, the detection of a subpopulation of clonogenic crypt cells which was resistant to killing by Ara-C has important clinical implications and warrants further investigation. These results are substantially different than those found after radiation where, with high radiation doses, the fraction of clonogenic crypt cells decreases exponentially, and where a close relation between reduction in clonogenic crypt cell survival and animal lethality has been established.

Original languageEnglish (US)
Pages (from-to)33-42
Number of pages10
JournalVirchows Archiv B Cell Pathology Including Molecular Pathology
Volume46
Issue number1
DOIs
StatePublished - Jan 1984
Externally publishedYes

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Cytarabine
Cell Survival
Radiation
S Phase
Maintenance
Morbidity
Acids
Water
Growth

Keywords

  • Animal lethality
  • Clonogenic crypt cells
  • Cytosine arabinoside
  • Drug resistance

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Medicine(all)

Cite this

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title = "Relationship between surviving clonogenic crypt fraction and animal lethality after cytosine arabinoside (Ara-C) exposure",
abstract = "We have measured animal morbidity and the fraction of clonogenic crypt cells following administration of several doses of Ara-C as an infusion over a 24 h period. A nonlinear relationship between reduction in crypt cell survival and Ara-C induced animal lethality was observed, indicating that factors other than crypt cell toxicity contribute to lethality in conventionally-maintained mice. A dose of 100 mg/kg Ara-C reduced the fraction of surviving clonogenic crypt cells to 7 × 10-3 without animal lethality. However, 300 mg/kg reduced crypt clonogenic cell survival only to 4× 10-3 while killing 50 percent of the animals. Maintenance of the animals on acid water before and after Ara-C treatment reduced animal lethality substantially. The magnitude of the reduction of clonogenic crypt cells was incompatible with S-phase specific toxicity as the only cytotoxic mechanism, and suggested that cell recruitment and crypt cell kill due to unbalanced growth are also operative during Ara-C infusion. In addition, the detection of a subpopulation of clonogenic crypt cells which was resistant to killing by Ara-C has important clinical implications and warrants further investigation. These results are substantially different than those found after radiation where, with high radiation doses, the fraction of clonogenic crypt cells decreases exponentially, and where a close relation between reduction in clonogenic crypt cell survival and animal lethality has been established.",
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AB - We have measured animal morbidity and the fraction of clonogenic crypt cells following administration of several doses of Ara-C as an infusion over a 24 h period. A nonlinear relationship between reduction in crypt cell survival and Ara-C induced animal lethality was observed, indicating that factors other than crypt cell toxicity contribute to lethality in conventionally-maintained mice. A dose of 100 mg/kg Ara-C reduced the fraction of surviving clonogenic crypt cells to 7 × 10-3 without animal lethality. However, 300 mg/kg reduced crypt clonogenic cell survival only to 4× 10-3 while killing 50 percent of the animals. Maintenance of the animals on acid water before and after Ara-C treatment reduced animal lethality substantially. The magnitude of the reduction of clonogenic crypt cells was incompatible with S-phase specific toxicity as the only cytotoxic mechanism, and suggested that cell recruitment and crypt cell kill due to unbalanced growth are also operative during Ara-C infusion. In addition, the detection of a subpopulation of clonogenic crypt cells which was resistant to killing by Ara-C has important clinical implications and warrants further investigation. These results are substantially different than those found after radiation where, with high radiation doses, the fraction of clonogenic crypt cells decreases exponentially, and where a close relation between reduction in clonogenic crypt cell survival and animal lethality has been established.

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