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Cytotoxic Effects of 1-β-D-Arabinofuranosyl-5-fluorocytosine and of 1-β-D-Arabinofuranosylcytosine in Proliferating Tissues in Mice¹

Division of Pharmacology, Sloan-Kettering Institute for Cancer Research, New York, New York 10021

1-β-D-Arabinofuranosyl-5-fluorocytosine (ara-FC), at doses lower than those generally used for the treatment of mouse leukemias, induces an immediate and complete inhibition of thymidine-2-¹⁴C or ³²P incorporation into DNA in mouse small intestine, spleen, and thymus, while not affecting ³²P incorporation into RNA. The inhibition is reversible and its duration is proportional to the dose given. Whereas karyorrhectic cells appear in the intestinal crypts and in lymph nodes, the spleen and thymus show no histologic effects. However, loss of prelabeled DNA from both spleen and thymus after administration of ara-FC indicates that cell destruction occurs in these organs. The extent of the pathologic process is related to the duration of DNA synthesis inhibition: doses of ara-FC that inhibit thymidine incorporation into DNA by more than 90% for at least 2 hours induce a maximal lesion while a shorter inhibition induces only minimal lesions. The cytotoxic effects are restricted to the proliferating zone of the crypt and to cells comparable in number to that of cells in S-phase. Similar results were obtained in mice given 1-β-D-arabinosylcytosine (ara-C). It is proposed that the lethal effects of ara-FC and ara-C are restricted to cells that are synthesizing DNA, that cells in other phases of the mitotic cycle escape damage, and that inhibition of DNA synthesis must be sustained for several hours in order to induce irreversible damage in sensitive S-phase cells.

¹ Aided by Grant CA 08748 from the National Cancer Institute, USPHS.

² Visiting Research Fellow from the Institute of Histology and General Physiology, University of Bologna, Italy.

Received 1/ 2/69. Accepted 6/11/69.

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