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Metabolism of 1-ß-D-Arabinofuranosylcytosine in L Cells¹

The Rockefeller Institute, New York, New York

1-ß-D-Arabinofuranosylcytosine inhibits mitosis and DNA³ synthesis, but not RNA or protein synthesis in mouse fibroblasts. This inhibition is irreversible in normal culture medium after treatment for as little as 2 hr with 10 µg/ml. Most cells die, and the survivors become grossly enlarged. Deoxycytidine, at concentrations 10–100 times as great, can prevent this lethal effect for a time and, within certain limits, partially reverse it; but deoxycytidine itself proves inhibitory with prolonged incubation.

Ara-C ultimately produces typical toxic effects in L cells even in the presence of deoxycytidine in large concentration. Ara-C is incorporated into DNA, and to a lesser extent into RNA. Replication of reovirus, a double-stranded RNA virus, is not inhibited by ara-C. It is postulated that the lethal effect of ara-C and its inhibition of continued DNA synthesis may be the result of its incorporation into DNA. This would probably result in configurational changes in a small region of helical DNA, with consequent failure of replication.

¹ Supported in part by Contract GM 10717, USPHS grant, NIH.

³ The abbreviations used are: ara-C, 1-ß-D-arabinofuranosylcytosine; ara-U, 1-ß-D-arabinofuranosyluracil; CR, cytidine; CdR, deoxycytidine; CDP, cytidine diphosphate; dCDP, deoxycytidine diphosphate; dCTP, deoxycytidine triphosphate IUDR, 5-iodo-2'-deoxyuridine; FUDR, fluorodeoxyuridine; RNA, ribonucleic acid; DNA, deoxyribonucleic acid; DNase, deoxyribonuclease; TCA, trichloroacetic acid; Tris, tris (hydroxymethyl) aminomethane; L cells, mouse fibroblasts.

² Present address: Division of Human Genetics, Department of Pedriatrics, Cornell University Medical College, New York, New York.

Received 1/11/65. Revised 5/ 6/65.