The inhibitory effects of N10-propargyl-5,8-dideazafolic
acid (
CB3717), a
quinazoline antifolate and a potent
thymidylate synthase inhibitor, were evaluated in human
leukemia cell lines resistant to
methotrexate (MTX) and
trimetrexate (TMQ). MTX-resistant MOLT-3 cell lines, MOLT-3/MTX200 and MOLT-3/MTX10,000, were cross-resistant to
CB3717; however, the degree of resistance was only tenfold for both cell lines, and increased
dihydrofolate reductase activity in MOLT-3/MTX10,000 had little influence on the degree of
CB3717 resistance. The MOLT-3 cell line made resistant to TMQ, MOLT-3/TMQ200, was as sensitive to
CB3717 as the parent line. The cell growth inhibitory effect of
CB3717 on MOLT-3 was reversed by the addition of
thymidine.
Leucovorin also partially reversed CB3717-induced growth inhibition. Cellular uptake of MTX and 5-methyl-tetrahydrofolate was hindered by the presence of a high concentration of
CB3717, whereas TMQ uptake was not influenced by
CB3717.
CB3717 appears to enter the cells not only through reduced
folate transport system, but by other route(s).
CB3717 does not share the transport pathway with TMQ. Our observations that MTX-resistant cells with increased
dihydrofolate reductase are not more resistant than cells without increased
enzyme activity, and that TMQ-resistant cells are not cross-resistant to
CB3717, may have clinical relevance.