Biochemical and pharmacologic rationale for high-dose methotrexate.

High-dose methotrexate (HDMTX) regimens were initially designed to overcome methotrexate (MTX) resistance due to defective transport of the drug. At high concentrations, enough MTX diffuses into resistant cells to saturate and inhibit the target enzyme, dihydrofolate reductase (DHFR). The high doses of MTX needed to achieve these high drug concentrations must be administered with the reduced folate antidote, leucovorin (LV; 5-formyltetrahydrofolate), to prevent increased toxicity. To increase MTX therapeutic index, LV rescue must be selective, i.e., more effective in normal than in tumor cells. In experimental models, selective rescue can be achieved if strict LV administration guidelines are respected. Since both MTX and LV use the membrane transport system, it was hypothesized that selective rescue occurred because transport-deficient, MTX-resistant tumor cells also transported LV poorly. The unsatisfactory clinical results frequently obtained with HDMTX regimens suggest a need to re-evaluate this underlying rationale, especially in view of recent findings concerning the mechanisms of MTX resistance and LV rescue. Experimentally, cells resistant to MTX because of an increased or altered DHFR, decreased metabolism to polyglutamates, or decreased thymidylate synthase activity are not always significantly more sensitive to higher concentrations of MTX. Furthermore, recent studies on human small cell lung cancer cell lines suggest that decreased MTX polyglutamate metabolism and thymidylate synthase activity might be prevalent MTX-resistant mechanisms in human tumors. Selective LV rescue could also occur through mechanisms other than selective uptake by normal tissues.(ABSTRACT TRUNCATED AT 250 WORDS)