Collateral methotrexate resistance in cisplatin-selected murine leukemia cells

Resistance to anticancer drugs is a major cause of failure of many therapeu tic protocols. A variety of mechanisms have been proposed to explain this p henomenon. The exact mechanism depends upon the drug of interest as well as the tumor type treated. While studying a cell line selected for its resist ance to cisplatin we noted that the cells expressed a >25,000-fold collater al resistance to methotrexate. Given the magnitude of this resistance we el ected to investigate this intriguing collateral resistance. From a series o f investigations we have identified an alteration in a membrane protein of the resistant cell as compared to the sensitive cells that could be the pri mary mechanism of resistance. Our studies reviewed here indicate decreased tyrosine phosphorylation of a protein (molecular mass = 66) in the resistan t cells, which results in little or no transfer of methotrexate from the me dium into the cell. Since this is a relatively novel function for tyrosine phosphorylation, this information may provide insight into possible pharmac ological approaches to modify therapeutic regimens by analyzing the status of this protein in tumor samples for a better survival of the cancer patien ts.