Purpose: To evaluate the novel taxane analogs, BMS-184476 and BMS-188797, as potential radiosensitizers in vitro and in vivo.
Methods and materials: Human H460 lung cancer cells were incubated with either paclitaxel or a taxane analog and irradiated at various times. Surviving fractions were then determined using a clonogenic assay. Three different schedules were used: (A) 1-h drug incubation with radiation at t = 8 h, (B) 1-h drug incubation with radiation at t = 24 h, (C) 24-h drug incubation with radiation immediately after. Cell cycle redistribution by taxanes alone was measured with propidium iodide and flow cytometry. Percent apoptosis was also measured using 7-aminoactinomycin D (7-AAD) staining with flow cytometry. For in vivo studies, H460 cell xenografts were used in nude mice. Tumors were grown s.c. on the flank and then treated with BMS-184476 (10 mg/kg i.p. injection, Days 0, 2, and 4) and/or radiation (2 Gy/day, Days 0-4). Tumor growth delay was then measured for each treatment group.
Results: The mean in vitro radiation dose enhancement ratios of BMS-184476, BMS-188797, and paclitaxel were 1.76, 1.49, and 1.31 for Schedules A, B, and C, respectively. Isobologram analysis showed that BMS-184476 was synergistic with radiation using Schedule A. Treatment with taxanes caused an increase in the percentage of G2/M cells at the time of irradiation. The mean fold increases in the %G2/M above control values for all three drugs were 5.6, 2.5, and 1.7 for Schedules A, B, and C, respectively. The combined effects of taxanes plus radiation on the induction of apoptosis were additive for all three drugs. In vivo studies showed that BMS-184476 can enhance the effects of fractionated radiotherapy, with an average enhancement factor of 1.66 obtained from three independent experiments.
Conclusions: These results demonstrated that the novel taxane analogs, BMS-184476 and BMS-188797, can enhance the effects of radiation in human lung cancer cells both in vitro and in vivo. These data also support the hypothesis that a G2/M block is involved in the radiosensitization caused by the taxanes.