Article Figures & Data
Figures
- Fig. 1.
A, the cytotoxicity of exisulind alone on the NSCLC line A549. B, the cytotoxicity of docetaxel alone and paclitaxel alone on the NSCLC line A549. C, the CI isobologram for the NSCLC line A549 adenocarcinoma treated in vitro with exisulind and paclitaxel. CI < 1 indicates synergism, CI = 1 indicates additive effects, and CI > 1 indicates antagonism. All data were obtained from 6-day MTT assays.
- Fig. 2.
First survival study of athymic nude rats with orthotopic A549 tumors. A, the survival curves for animals treated with exisulind and docetaxel alone compared with saline-treated controls (+); exisulind 50 mg/kg alone (▵); exisulind 100 mg/kg alone (▴); docetaxel 5 mg/kg (2×) then 2.5 mg/kg (4×; ○); and docetaxel 10 mg/kg (2×) and 5 mg/kg (4×; •). B, the survival curves for animals treated with the combination of exisulind + docetaxel compared with saline treated controls (+); exisulind 50 mg/kg plus docetaxel 5 mg/kg (2×) then 2.5 mg/kg (4×; ▿); exisulind 100 mg/kg plus docetaxel 5 mg/kg (2×) then 2.5 mg/kg (4×; ▾); exisulind 50 mg/kg plus docetaxel 10 mg/kg (2×) then 5 mg/kg (4×; □); and exisulind 100 mg/kg plus docetaxel 10 mg/kg (2×) then 5 mg/kg (4×; ▪).
- Fig. 3.
Second survival study of athymic nude rats with orthotopic A549 tumors. A, the survival curves for animals treated with exisulind or docetaxel alone compared with saline treated controls (+); exisulind 25 mg/kg alone (▵); exisulind 50 mg/kg alone (▴); docetaxel 2.5 mg/kg (6×; ○); and docetaxel 5 mg/kg (6×; •). B, the survival curves for animals treated with exisulind + docetaxel compared with saline treated controls (+); exisulind 25 mg/kg plus docetaxel 2.5 mg/kg (6×; ▿); exisulind 25 mg/kg plus docetaxel 5 mg/kg (6×; ▾); exisulind 50 mg/kg plus docetaxel 2.5 mg/kg (6×; □); exisulind 50 mg/kg plus docetaxel 5 mg/kg (6×; ▪); and exisulind 50 mg/kg plus docetaxel 5 mg/kg (2×) then 2.5 mg/kg (4×; ♦).
- Fig. 4.
Dissected lungs and mediastinum from athymic nude rats with A549 tumors treated with (A) saline control (day 34), (B) exisulind 50 mg/kg (day 55), (C) docetaxel 5 mg/kg (day 50), and (D) exisulind 50 mg/kg plus docetaxel 5 mg/kg (day 80).
- Fig. 5.
Apoptotic rates determined by TUNEL analysis. The levels of apoptosis in the treatment groups were compared with the background apoptosis levels in the control group that received no treatment. Levels of apoptosis relative to controls are shown. The treatment group receiving the combination of 50 mg/kg/day of exisulind and 5 mg/kg/day docetaxel exhibited a significant increase in apoptosis.
Tables
- Table 1
In vitro effects of exisulind and docetaxel alone and in combination on cell cycle distribution and % of apoptotic cells in A549 NSCLC cells
Treatment % G1a % S % G2-M % Apoptosis Control 24 h 46 38 16 0 Exi 200 μm 60 22 18 0.1 Exi 300 μm 65 14 21 0 Doce 0.2 nm 42 39 19 0 Doce 0.5 nm 38 41 21 0.05 Doce 1 nm 46 40 14 0.58 Doce 3 nm 32 57 11 11 Control 12 h 51 33 16 0 Docetaxel 6 nm 30 50 20 34 Docetaxel 10 nm 10 51 39 64 Control 24 h 46 38 16 0 Exi 200 μm + Doce 0.2 nm 59 21 20 0.47 Exi 200 μm + Doce 0.5 nm 54 28 19 9.4 Exi 200 μm + Doce 1 nm 46 8 46 5 Exi 300 μm + Doce 0.2 nm 58 17 25 5 Exi 300 μm + Doce 0.5 nm 43 24 33 39 Exi 300 μm + Doce 1 nm 51 36 13 62 -
a Exi, exisulind; Doce, docetaxel; % Apoptosis, percentage of apoptotic cells.
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- Table 2
Effect of exisulind, docetaxel, and the combination on the number of athymic rats with metastases from orthotopic A549 tumors (first experiment)
Treatment Dose and schedule Mean survival days (P, log-rank) # rats with mets/# treated (P, Fisher’s exact test) Control 43 days 9/10 Exisulind 50 mg/kg daily 52.5 days 7/8 (P = 0.49) (P = 1.0) Exisulind 100 mg/kg daily 57.625 days 7/8 (P = 0.26) (P = 1.0) Docetaxela 5 mg/kg (2×/wk) 63.5 days 6/8 2.5 mg/kg/wk (4×) (P = 0.058) (P = 0.56) Docetaxela 10 mg/kg (2×/1 wk) 63.25 days 5/8 5 mg/kg/wk (4×) (P = 0.038) (P = 0.27) Exisulind 50 mg/kg daily >80 days 1/8 Docetaxela 5 mg/kg (2×/wk) (P < 0.001) (P = 0.003) 2.5 mg/kg/wk (4×) Exisulind 50 mg/kg daily 62.375 days 3/8 Docetaxela 10 mg/kg (2×/wk) (P = 0.12) (P = 0.043) 5 mg/kg/wk (4×) Exisulind 100 mg/kg daily 43.375 days 4/8 Docetaxela 5 mg/kg (2×/wk) (P = 0.99) (P = 0.12) 2.5 mg/kg/wk (4×) Exisulind 100 mg/kg daily 49 days 3/8 Docetaxela 10 mg/kg (2×/wk) (P = 0.40) (P = 0.043) 5 mg/kg/wk (4×) -
a Docetaxel was administered at the higher dose twice in the first week and once weekly at the lower dose for the next 4 weeks.
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- Table 3
Effect of exisulind, docetaxel, and the combination on the number of athymic rats with metastases from orthotopic A549 tumors (second experiment)
Treatment Dose and schedule Mean survival days (P, log-rank) # rats with mets/# treated (P, Fisher’s exact test) Control 35.7 days 15/15 Exisulind 25 mg/kg daily 36 days 12/12 (P = 0.76) (P = 1.0) Exisulind 50 mg/kg daily 41.08 days 11/12 (P = 0.31) (P = 0.41) Docetaxel 2.5 mg/kg/wk (6×) 34.5 days 12/12 (P = 0.66) (P = 1.0) Docetaxel 5 mg/kg/wk (6×) 43.58 days 9/12 (P = 0.17) (P = 0.06) Exisulind 25 mg/kg daily 35.5 days 12/12 Docetaxel 2.5 mg/kg/wk (6×) (P = 0.68) (P = 1.0) Exisulind 25 mg/kg daily 49.33 days 8/12 Docetaxel 5 mg/kg/wk (6×) (P = 0.04) (P = 0.02) Exisulind 50 mg/kg daily 36 days 11/12 Docetaxel 2.5 mg/kg/wk (6×) (P = 0.31) (P = 0.41) Exisulind 50 mg/kg daily 63.17 days 2/12 Docetaxel 5 mg/kg/wk (6×) (P < 0.0004) (P < 0.0001) Exisulind 50 mg/kg daily 65.17 days 1/12 Docetaxela 5 mg/kg/wk (3×) (P < 0.0001) (P < 0.0001) 2.5 mg/kg/wk (3×) -
a Docetaxel was administered at 5 mg/kg/wk for the weeks 1–3 and at the lower dose of 2.5 mg/kg/wk for weeks 4–6.
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Volume 8, Issue 3
