Kinetic Analysis of Combination Effect of Navelbine (KW‐2307) with Cisplatin against Human Lung Adenocarcinoma PC‐12 Cells in Culture

The combination effect of navelbine (NVB, KW‐2307), a newly synthesized vinca alkaloid, and cisplatin (CDDP) was compared with that of vindesine (VDS) and CDDP using human lung adenocarcinoma PC‐12 cells. The growth‐inhibitory activity of NVB or VDS was time‐dependent, whereas that of CDDP was AUC (area under the curve)‐dependent. When NVB or VDS was used in combination with CDDP simultaneously for 24 h, antagonism was observed in terms of growth‐inhibitory activity. However, additive combination effect was observed when NVB or VDS treatment was followed by CDDP treatment. On this treatment schedule, a synergistic combination effect was observed in terms of the cell‐killing activity assessed by colony formation assay. The growth‐inhibitory activity of NVB or VDS was detected 24 h after the treatment, whereas that of CDDP became significant 72 h after the treatment. NVB and VDS caused cell accumulation in G2M phase at 10 times their IC(80) values, and cells with less than diploid DNA content were detected after 24 h at IC(80). CDDP caused accumulation of cells in S phase, and the effect became detectable 16 h after the treatment. The DNA histogram of cells treated with NVB or VDS in combination with CDDP was a superposition of those of cells treated with each drug alone. Significant differences in the characteristics of anticellular activity were not detected between NVB and VDS, although NVB inhibited cell growth at a slightly lower concentration than VDS at the short exposure time of 1–8 h.