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Departments of Medicine and Molecular Pharmacology, the Albert Einstein College of Medicine, and the Einstein Cancer Research Center, Bronx, New York
A methotrexate (MTX)-resistant HeLa subline (R5), developed in this laboratory, with impaired transport due to a genomic deletion of the reduced folate carrier (RFC) was only 2-fold resistant to pemetrexed (PMX), but 200- and 400-fold resistant to raltitrexed (ZD1694) and N
-(-4-amino-4-deoxypteroyl)-N
-hemiphthaloyl-1-ornithine (PT523), respectively, compared with parental HeLa cells when grown with 2 µM folic acid. When folic acid was replaced with the more physiological 25 nM 5-formyltetrahydrofolate, R5 cells were 2-fold collaterally sensitive to PMX but still 40- and 200-fold resistant to ZD1694 and PT523, respectively. Sensitivity to PT523 and PMX could be completely restored, and sensitivity to ZD1694 nearly restored, by transfection of RFC cDNA into R5 cells, indicating that the defect in drug transport was the only, or major, factor in resistance. The preserved PMX activity in R5 cells could not be related to the very low expression of folate receptors. Rather, retained PMX activity in R5 cells was associated with residual transport by another process that exhibits good affinity for PMX (Kt = 12 µM) with much lower affinities for ZD1694, MTX, and PT523 (Kis of 
90, 100, and 250 µM, respectively). PMX transported by this route was rapidly converted to higher polyglutamates and, when grown with 25 nM 5-formyl-tetrahydrofolate, the rate of formation of these derivatives and their net accumulation in R5 cells was comparable to that of wild-type cells. These data suggest that selective preservation of PMX pharmacological activity in RFC-null R5 cells is due, in part, to partial preservation of transport by secondary process with a higher affinity for PMX than the other antifolates evaluated.
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