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Drug exposure impacts the antitumor activity for many chemotherapy agents. Maximum drug concentrations (Cmax), Area Under the Curve (AUC), and steady state concentrations (Css) may influence antitumor activity. Fixed dose rate (continuous) gemcitabine infusion is superior to short infusion for patients with pancreatic adenocarcinoma, but has not been demonstrated for non-small cell lung cancer (NSCLC). We have developed an in vitro bioreactor tissue culture system that allows for changing drug exposure to mimic measured changes in in vivo drug concentrations. H2009 cells were grown in the extracapillary space (E.C.S.), and gemcitabine was infused as 3 mg with a syringe pump over either 0.5 (n=5) or 2.5 hr (n=5), followed by mono-exponential elimination to simulate clinically relevant plasma concentrations. Gemcitabine concentrations were measured and cell death was assessed by flow cytometry and colony forming assay (CFA) five days after treatment. For the 0.5 hr infusion, the Cmax was (Mean ± SD) 50.8 ± 10.9 μM, clearance was 4.53 ± 0.14 mL/minand the AUC was 33.2 ± 6.21 μM*hr. For continuous infusions (n=5), the Cmax was 15.4 ± 3.91 μM, Css was 13.0 ± 0.25, clearance was 4.49 ± 0.08 mL/min, and the AUC, 38.5 ± 9.75 μM*hr. SubG1 were as follows: 42.3 ± 12% 0.5 hr control, 69.6 ± 10% 0.5 hr gemcitabine, 57.2 ± 19.6% 2.5hr control, and 78.2 ± 19.6% 2.5 hr gemcitabine. TUNEL data were as follows: 16.6 ± 7.27% 0.5 hr control, 41.4 ± 16.8% 0.5 hr gemcitabine, 24.8 ± 12.8% 2.5 hr control, and 42.6 ± 19.6% 2.5 hr gemcitabine. CFA survival as follows: 7.08 ± 3.46% 0.5 hr control, 2.12 ± 1.30% 0.5 hr gemcitabine, 4.73 ± 2% 2.5 hr control, and 0.09 ± 0.03% 2.5 hr gemcitabine. Normalized to controls, survival was 15-fold lower for the continuous relative to the short infusion. Studies are on-going to evaluate cellular gemcitabine tri-phosphorylated metabolite amounts, to evaluate cell density on the hollow fibers by microscopy, and to minimize non-drug related cell death. This system can be used to determine the effects of Cmax and Css on the induction of cell death, and enables us to characterize optimal exposure-response relationships for investigational agents. Supported by Cancer and Leukemia Group B Junior Faculty Research Award.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA