Transport and metabolism of 1-beta-D-arabinofuranosylcytosine in human ovarian adenocarcinoma cells.
1-beta-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 microM 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 microM araC were 5-fold less in ovarian than in leukemic cells. The major metabolic product of araC was 1-beta-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.
Jamieson
G P
GP
Department of Haematology, Austin Hospital, Heidelberg, Melbourne, Australia.
Snook
M B
MB
Bradley
T R
TR
Bertoncello
I
I
Wiley
J S
JS
D000230:Adenocarcinoma / Q000378:metabolism*; D000368:Aged; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D003561:Cytarabine / Q000378:metabolism*; D005260:Female; D006801:Humans; D015479:Leukemia, Myelomonocytic, Acute / Q000378:metabolism; D008297:Male; D010051:Ovarian Neoplasms / Q000378:metabolism*; D013868:Thioinosine / Q000031:analogs & derivatives / Q000378:metabolism
D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D013868:Thioinosine; C001789:4-nitrobenzylthioinosine