Role of polyglutamates in methotrexate action.

Numerous cell systems and tissues contain methotrexate (MTX) polyglutamates after MTX and HDMTX (high dose) treatment. The formation of MTX polyglutamates is concentration- and time-dependent. Great differences in the length of the poly-y-glutamyl side chains are observed. Efflux kinetics of MTX and MTX polyglutamates vary considerably depending on the kind of cells and the length of the side chain. In erythrocytes accumulation of MTX and MTX polyglutamates results in intracellular concentrations much higher than the serum MTX levels. Efflux differences with long-lasting storage of the polyglutamate forms of MTX up to the total life-span of the single erythrocyte. Even 6-14 days after HDMTX therapy, high MTX levels could be determined in sarcoma tissue. In each case besides unchanged MTX there was a formation of MTX polyglutamates. The portion of polyglutamates varied considerably, amounting from 3% to 68% of total tumor MTX. A relation between the formation of MTX polyglutamates and the clinical effectiveness of HDMTX therapy seems to be possible. MTX polyglutamates play a major role in the principles and effectiveness of HDMTX therapy.