Schedule-dependent synergism of vinorelbine and 5-fluorouracil/UFT against non-small cell lung cancer

Elderly patients with advanced non-small cell lung cancer (NSCLC) require chemotherapy that is effective and minimally toxic. We evaluated the activity of a combination of vinorelbine and 5-fluorouracil (5-FU)/UFT (a fixed combination of tegafur and uracil) in vitro and in vivo to establish a rationale for clinical use. The cytotoxic activities of various combinations of vinorelbine and 5-FU, the active metabolite of tegafur, were analyzed by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazlium bromide (MTT) assay and isobologram technique in vitro, using 3 NSCLC cell lines (A549, PC14, and Ma10). Sequential exposure to vinorelbine followed by 5-FU showed additive or synergistic activity against all 3 NSCLC cell lines tested. The reverse sequence showed no synergism. Antitumor activity and survival prolongation after treatment with different combinations of vinorelbine and UFT were evaluated in nude mice bearing PC14 xenografts. Treatment with vinorelbine before UFT was associated with higher antitumor activity, less toxicity, and longer survival than the reverse sequence. To clarify the underlying mechanism by which the combination exerts the synergistic effects, the expression of thymidylate synthase (TS) was assessed by Western blot analysis in vitro and by immunohistochemical analysis in an animal model. Vinorelbine suppressed the 5-FU-induced increase in TS protein in A549 cells. In PC14 tumor tissues of animal models, TS expression in cancer cells was suppressed by vinorelbine. Our data suggest that treatment with vinorelbine injection before oral UFT may have synergistic activity against NSCLC. This synergistic activity may be attributed to increased chemosensitivity to UFT caused by vinorelbine-induced suppression of TS.