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

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.