SELECTIVE TOXICITY OF A NEW LIPOPHILIC ANTIFOLATE, BW301U, FOR METHOTREXATE-RESISTANT CELLS WITH REDUCED DRUG UPTAKE

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  • 1 January 1985
    • journal article
    • research article
    • Vol. 45  (3) , 978-982
Abstract
Three methotrexate (MTX)-resistant cell lines and their MTX-sensitive counterparts were used to examine 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methyl-pyrido[2,3-d]pyrimidine (BW301U), a novel lipophilic antifolate and compare its cytotoxicity with MTX and metoprine. Collateral sensitivity for both BW301U and metoprine was observed in CCRF-CEM/MTX R-cells, where MTX resistance appeared to be primarily due to a deficiency in drug uptake. This was particularly pronounced with BW301U which proved to be as effective in killing CCRF-CEM/MTX R as was MTX with the parental CCRF-CEM cell line. This effect was not seen in other cell lines, L5178Y/MTX or L1210/MTX R, where resistance to MTX was correlated with either an overproduction of 5,6,7,8-tetrahydrofolate:NADP oxidoreductase [EC 1.5.1.3 (DHFR)] or with combined uptake defect and increased DHFR levels, respectively. In each case, however, BW301U and metoprine, especially at high concentrations, were more effective than MTX in treating MTX-resistant cells.