Collateral sensitivity of cisplatin-resistant human lung cancer cell lines to thymidylate synthase inhibitors

The sensitivity of three cisplatin-resistant human non-small cell lung cancer cell lines, PC-7/1.0, PC-9/0.5, and PC-14/1.5 cells, to 5-fluorouracil was compared with that of the parental cell lines. The 50% inhibitory concentrations (IC₅₀) value of 5-fluorouracil for PC-7/1.0 cells was 4.3-fold (p < 0.01) lower than that of the parental cell line. PC-9/0.5 and PC-14/1.5 cells showed a similar tendency without statistical significance. The IC₅₀ values of other thymidylate synthase inhibitors, 5-fluoro-2'-deoxyuridine and trifluorothymidine, were lower for PC-7/1.0, PC-9/0.5 and PC-14/1.5 cells than for their parental cell lines. The mechanisms of collateral sensitivity to 5-fluorouracil were examined in PC-7/1.0 cells. Thymidylate synthase activity was determined by fluorodeoxyuridine monophosphate (FdUMP) binding activity and no consistent difference between cisplatin-resistant and parental cell lines was found. The inhibition of thymidylate synthase after exposure to 10 μg/ml of 5-fluorouracil for 6 h was higher in PC-7 (84.1%) than PC-7/1.0 (51.3%) cells. Thus, there is no direct correlation in these cell lines between the sensitivity to inhibition of thymidylate synthase by 5-fluorouracil and 5-fluorouracil cytotoxicity. Incorporation of [³H]-thymidine into DNA was lower in PC-7/1.0 compared to PC-7 cells without a significant difference in thymidine kinase activity. We speculate that the decrease in salvage synthesis of thymidylate was a possible reason for the collateral sensitivity of PC-7/1.0 cells.