Collateral methotrexate resistance in cisplatin-selected murine leukemia cells.
Resistance to anticancer drugs is a major cause of failure of many therapeutic protocols. A variety of mechanisms have been proposed to explain this phenomenon. The exact mechanism depends upon the drug of interest as well as the tumor type treated. While studying a cell line selected for its resistance to cisplatin we noted that the cells expressed a > 25,000-fold collateral resistance to methotrexate. Given the magnitude of this resistance we elected to investigate this intriguing collateral resistance. From a series of investigations we have identified an alteration in a membrane protein of the resistant cell as compared to the sensitive cells that could be the primary mechanism of resistance. Our studies reviewed here indicate decreased tyrosine phosphorylation of a protein (molecular mass = 66) in the resistant cells, which results in little or no transfer of methotrexate from the medium into the cell. Since this is a relatively novel function for tyrosine phosphorylation, this information may provide insight into possible pharmacological approaches to modify therapeutic regimens by analyzing the status of this protein in tumor samples for a better survival of the cancer patients.
Bhushan
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A
Department of Pharmaceutical Sciences, College of Pharmacy, Idaho State University, Pocatello 83209-8334, USA.
Hacker
M P
MP
Tritton
T R
TR
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D002945:Cisplatin / Q000009:adverse effects / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D007939:Leukemia L1210 / Q000188:drug therapy*; D008727:Methotrexate / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D010766:Phosphorylation; D014443:Tyrosine / Q000494:pharmacology
D000970:Antineoplastic Agents; D014443:Tyrosine; D002945:Cisplatin; D008727:Methotrexate