Js. Kim et al., 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, INT J RAD O, 51(2), 2001, pp. 525-534
Citations number
38
Categorie Soggetti
Radiology ,Nuclear Medicine & Imaging","Onconogenesis & Cancer Research
Journal title
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
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.