The effects of cytosine arabinoside upon proliferating epithelial cells.

Experiments were conducted to obtain additional insight into the response patterns of the intestinal crypts to 1-0-D-arabinofuranosylcytosine, a potent inhibitor of DNA synthesis. The results indicate that this interference with nucleic acid metabolism is not lethally toxic to the crypt epithelial cells. This formulation is based on the following observations: (a) the absence of definitive ultrastructural manifestations of irreversible cell damage, particularly with respect to the nucleus; (b) the presence of labeled thymidine in virtually 100% of the mitotic figures occurring during recovery from the inhibitory effects of the analog; (c) the enhanced mitotic activity which closely followed the resumption of a considerable degree of DNA synthesis; (d) the failure to find any indication of intestinal epithelial cell death in animals killed 24 and 48 hr after the first of multiple injections of l-(3-D-arabinofuranosylcytosine; and (e) the absence of histolÃ3gica! evidence of cell death in a number of other epithelial tissues programmed for continuous replication. In contrast, however, stigmata of severe cytotoxic effects were readily discernible in the intestinal lymphocytes. It is therefore concluded that the apparent necrosis of the intestinal crypts noted with conventional microscopy actually represents phagocytosis of degenerating lymphocytic elements by adjacent crypt epithelial cells.