Abstract A21: Preclinical bioanalytical development to optimize drug treatment regimens using orthotopic models of human gastric cancer

Gastric cancer remains the second leading cause of cancer deaths worldwide and while gains have been made its treatment including neo‐ and post‐ adjuvant chemotherapy response rates are variable with limited survival benefit. Recent identification of molecular markers important in the pathogenesis of gastric cancer has spurred development of standard and targeted therapies to treat gastric cancer; however, lack of validated models has hindered this effort. Preclinical development of anticancer agents can be accelerated with better tools to optimize a treatment regimen for in vivo studies. Identifying a useful drug concentration, route of administration and treatment schedule is costly and time consuming and often the decided regimen is suboptimal for efficacy experiments. To address these issues, we have developed and characterized two cell‐based orthotopic gastric tumor xenograft models (MKN‐45 and 23132‐87) in nude mice and rats. Using the mouse models we compared efficacy of several relevant anticancer agents including cisplatin, trastuzumab, docetaxel, ixabepilone, capecitabine and lapatinib. Bioanalytical methods using a UPLC‐MS/MS system were developed for the latter four agents. Drug plasma concentrations were analyzed using blood collected at multiple in study timepoints from each animal ( 85% versus control. However, 23132‐87 was insensitive to cisplatin and ixabepilone as well as trastuzumab and lapatinib but not capecitabine (TGI=79%) which was ineffective towards the MKN‐45 model (T/C=19%). Bioanalytical analysis yielded Cmax values for each agent and steady state concentrations and plasma to tumor concentration ratios determined for capecitabine and lapatinib. Results from these studies confirm two useful orthotopic models of gastric cancer with variable drug sensitivity. We have developed a platform for testing new drugs which can be tailored to optimize treatment regimen parameters and correlate with efficacy in a single study. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A21.