CORRELATION OF ALTERED TYROSINE PHOSPHORYLATION WITH METHOTREXATE RESISTANCE IN A CISPLATIN-RESISTANT SUBLINE OF L1210 CELLS

Collateral resistance to cisplatin and methotrexate has been reported in several cell lines. A murine leukemia cell line (L1210/DDP) selecte d for cisplatin resistance also has been shown to be highly resistant to methotrexate. Of the mechanisms proposed for methotrexate resistanc e, only changes in methotrexate transport into the cells were found in an earlier report. Methotrexate enters mammalian cells via an active transport system. In the present study, we demonstrated that the trans port into the cell may be impaired in the resistant cells due to alter ed tyrosine phosphorylation of a membrane protein with a molecular mas s of 66 kDa. This alteration was manifested by altered tyrosine phosph orylation of the 66 kDa protein and may be an underlying modification that renders the cells resistant to methotrexate. These results sugges t involvement of tyrosine phosphorylation in folate transport and meth otrexate resistance in L1210/DDP cells.