Abstract
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Apo2L/TRAIL is a member of the tumor necrosis factor superfamily that induces apoptosis in various types of cancer cells but not in most normal cells. We developed an orthotopic lung cancer model by injection of human NCI-H460 non-small cell. lung carcinoma cells (1 million) directly into the left lung of nude mice, and tested the effect of recombinant soluble Apo2L/TRAIL on tumor growth. After allowing tumors to develop over 10 days, mice were randomized and treated with vehicle, or Apo2L/TRAIL (60 mg/kg/day IP for 2 weeks), or chemotherapy (Taxol 6.25 mg/kg/day SC for 5 days, plus Carboplatin 100 mg/kg single IP dose), or the combination of both. On day 24 after tumor cell injection, the lungs were removed and tumor sizes were determined. Apo2L/TRAIL or chemotherapy reduced mean tumor size by 60%, (P=0.0132, n=10) or 57% (P=0.0189, n=10), respectively, as compared to vehicle control (n=9), while the combination treatment reduced tumor size by 97% (P=0.0002, n=10). In a separate study, mice were treated as described above, and survival was followed for 3 months. Day 90 survival was 6.7 %, 20.0%, 21.4%, or 46.7% in the vehicle, Apo2L/TRAIL, chemotherapy, or combination treatment group, respectively. Mantel-Cox analysis of survival plots indicated that the effect of either monotherapy did not reach statistical significance, while combination treatment significantly improved survival vs. control (P=0.0003) and vs. chemotherapy alone (P=0.035). These preclinical studies provide the first evidence that Apo2L/TRAIL can exert in vivo activity against lung tumors and underscore the potential of this agent to cooperate with established chemotherapy for the treatment of lung cancer.
[Proc Amer Assoc Cancer Res, Volume 45, 2004]
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