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Transport and Metabolism of 1-ß-D-Arabinofuranosylcytosine in Human Ovarian Adenocarcinoma Cells¹

Department of Haematology [G. P. J., M. B. S., J. S. W.], Austin Hospital, Heidelberg, Melbourne, 3084; and Cell Biology Group [T. R. B., I. B.], Peter MacCallum Cancer Institute, Melbourne, 3000; Australia

1-ß-D-Arabinofuranosylcytosine (araC) is an effective drug in the i.p. therapy of ovarian carcinoma but little is known of its transport and metabolism in this tumor. Influx of araC at 1 µM into cultured human ovarian carcinoma cells (CI 80-13S) was largely inhibited by nanomolar concentrations of the nucleoside transport inhibitor, nitrobenzylthioinosine, while the residual influx (approximately 10%) was inhibited only by micromolar concentrations of nitrobenzylthioinosine. There was a two fold greater density of specific [³H]nitrobenzylthioinosine binding to the nucleoside transporters on the ovarian than on cultured human leukemic cells (RC2a). Calculated turnover rates of the nucleoside transporter for 1 µM araC were 5-fold less in ovarian than in leukemic cells. The major metabolic product of araC was 1-ß-D-arabinofuranosylcytosine 5'-triphosphate (araCTP) which accumulated in the ovarian cells to levels half those achieved in the leukemic cells. AraC was the major product of araCTP degradation in ovarian cells consistent with a pathway (araCTP araCMP araC) which is different from that previously found in leukemic cells (araCTP araCMP araUMP araU). Despite these differences, ovarian carcinoma cells show substantial accumulation of araCTP from extracellular araC.

¹ This work was carried out during the tenure of a grant from the Anti-Cancer Council of Victoria. We also thank The Upjohn Company for their support.

² To whom requests for reprints should be addressed.

Received 2/23/88. Revised 8/ 4/88. Accepted 9/26/88.

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