The novel taxane analogs, BMS-184476 and BMS-188797, potentiate the effects of radiation therapy in vitro and in vivo against human lung cancer cells

Purpose: To evaluate the novel taxane analogs, BMS-184476 and BMS-188797, a s potential radiosensitizers in vitro and in vivo. Methods and Materials: Human H460 lung cancer cells were incubated with eit her paclitaxel or a taxane analog and irradiated at various times. Survivin g 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 w ith radiation immediately after. Cell cycle redistribution by taxanes alone was measured with propidium iodide and flow cytometry. Percent apoptosis w as also measured using 7-aminoactinomycin D (7-AAD) staining with flow cyto metry. For in vivo studies, H460 cell xenografts; were used in nude mice. T umors 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, an d C, respectively. Isobologram analysis showed that BMS-184476 was synergis tic with radiation using Schedule A. Treatment with taxanes caused an incre ase in the percentage of G2/M cells at the time of irradiation. The mean fo ld 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 effect s 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 ef fects 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 can enhance the effects of radiation in human lu ng cancer cells both in vitro and in vivo. These data also support the hypo thesis that a G2/M block is involved in the radiosensitization caused by th e taxanes. (C) 2001 Elsevier Science Inc.