TY - JOUR
T1 - Dipyridamole inhibits reversion by thymidine of methotrexate effect and increases drug uptake in Sarcoma 180 cells
AU - Cabral, S.
AU - Leis, S.
AU - Bover, L.
AU - Nembrot, M.
AU - Mordoh, J.
PY - 1984
Y1 - 1984
N2 - The combined effect of methotrexate (MTX) with dipyridamole, an inhibitor of nucleoside transport, was studied in ascitic Sarcoma 180 cells. It was determined that 10 μM MTX inhibits by >90% deoxy[3H]uridine incorporation into DNA and that this MTX concentration inhibits DNA synthesis as revealed by deoxy[3H]cytidine but not [3H]thymidine incorporation into DNA. Exogenous thymidine (≥ 1μM) in the cell culture medium enhances DNA synthesis in nontreated cells and fully restores it in MTX-treated cells, whereas hypoxanthine has no appreciable effect on DNA synthesis. Dipyridamole inhibits deoxy[3H]cytidine and [3H]thymidine uptake by these cells (IC50 = 0.2 and 3 μM, respectively) and blocks the increase in TTP pool produced by 1 μM thymidine in MTX-treated cells (23.1 ± 4.7 pmol per 1 x 106 cells vs 80.4 ± 18.9 pmol per 1 x 106 cells). Dipyridamole at 10 μM enhances [3H]MTX accumulation by Sarcoma 180 cells and diminishes the efflux of the drug in previously loaded cells. It is suggested that the combination of inhibitors of the de novo pathway for pyrimidine biosynthesis, such as MTX, with inhibitors of the salvage pathway, such as dipyridamole, may increase the cytotoxic activity of MTX alone.
AB - The combined effect of methotrexate (MTX) with dipyridamole, an inhibitor of nucleoside transport, was studied in ascitic Sarcoma 180 cells. It was determined that 10 μM MTX inhibits by >90% deoxy[3H]uridine incorporation into DNA and that this MTX concentration inhibits DNA synthesis as revealed by deoxy[3H]cytidine but not [3H]thymidine incorporation into DNA. Exogenous thymidine (≥ 1μM) in the cell culture medium enhances DNA synthesis in nontreated cells and fully restores it in MTX-treated cells, whereas hypoxanthine has no appreciable effect on DNA synthesis. Dipyridamole inhibits deoxy[3H]cytidine and [3H]thymidine uptake by these cells (IC50 = 0.2 and 3 μM, respectively) and blocks the increase in TTP pool produced by 1 μM thymidine in MTX-treated cells (23.1 ± 4.7 pmol per 1 x 106 cells vs 80.4 ± 18.9 pmol per 1 x 106 cells). Dipyridamole at 10 μM enhances [3H]MTX accumulation by Sarcoma 180 cells and diminishes the efflux of the drug in previously loaded cells. It is suggested that the combination of inhibitors of the de novo pathway for pyrimidine biosynthesis, such as MTX, with inhibitors of the salvage pathway, such as dipyridamole, may increase the cytotoxic activity of MTX alone.
UR - http://www.scopus.com/inward/record.url?scp=0021252939&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0021252939&partnerID=8YFLogxK
U2 - 10.1073/pnas.81.10.3200
DO - 10.1073/pnas.81.10.3200
M3 - Article
C2 - 6587345
AN - SCOPUS:0021252939
SN - 0027-8424
VL - 81
SP - 3200
EP - 3203
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 10 I
ER -