@entity421 cells, resistant to @entity1499 due to @entity2353 and nucleobase salvage, are sensitive to XXXX analogs.

@entity1 @entity2642 @entity2353 @entity137 @entity12948 @entity3625 @entity377 @entity4341 @entity2592 @entity421 @entity1500 @entity1014 @entity1499
PURPOSE: To test a novel strategy for overcoming intrinsic resistance to @entity1499 ( @entity1500 ) in @entity421 ( @entity421 ) due to @entity2353 and nucleobase salvage (NS). METHODS: Four @entity421 cell lines, found to be highly resistant to @entity1500 , were tested to determine the dominant mechanism of resistance. Sensitivity to @entity1500 was tested in the presence of dialyzed serum or the transport inhibitor @entity4341 (DP) to confirm the contribution of NS to @entity1500 resistance. We then investigated whether increased NS activity could be exploited using cytotoxic @entity2353 analogs. RESULTS: Like other cell types, @entity421 cells are capable of circumventing inhibition of de novo @entity377 synthesis by relying on NS. @entity1500 , at concentrations as high as 1 m M did not inhibit cell growth in culture medium supplemented with undialyzed serum. In contrast, when NS was inhibited by DP or in medium depleted of @entity2642 and nucleobases, sensitivity to @entity1500 was seen at nanomolar concentrations. In medium with dialyzed serum, @entity1014 and @entity3625 provided dose-dependent protection from @entity1500 @entity137 at concentrations similar to those seen in @entity1 plasma. No evidence of other significant mechanisms of resistance were found. All four cell lines were sensitive to 3-day exposures to @entity2592 (IC50 0.22 to 2.88 micro M) and @entity12948 (IC50 0.09 to 0.95 micro M). CONCLUSIONS: Salvage of de novo @entity377 synthesis inhibition by extracellular @entity1014 and @entity3625 , at physiologically relevant concentrations, contributes to resistance to @entity1500 in @entity421 . However, this same process may impart a collateral sensitivity to @entity2353 analogs. These findings support clinical trials for @entity1 with @entity421 using @entity2353 analogs, either alone or in combination.
