Establishment of human primary non-small cell lung cancer xenograft models for test of cytotoxic and targeted anticancer drugs

Abstract

11008 Background: New oncology drug development has moved from general cytotoxic agents to molecular target-directed therapeutics. Consequently, there is a need to identify tumor types and individual patient tumors that express the target and could benefit from more selective therapies in clinical trials. Therefore, the in vivo models used in preclinical development should be“disease-oriented” and target-directed. Recently, we developed non-small cell lung cancer (NSCLC) xenograft models by transplanting human fresh tumor fragments into nude mice, which have been used for test of cytotoxic and targeted anticancer drugs. Methods: The fresh NSCLC tumors were collected from local hospitals. The tumor fragments were subcutaneously implanted into nude mice. The EGFR and K-ras mutation status of the tumors were investigated and compared with the efficacy results. The test drugs included paclitaxel, gemcitabine, and the epidermal growth factor receptor (EGFR) inhibitor erlotinib. Results: A total of 72 NSCLC samples were implanted, and 13 tumor models were established (tumor taking rate 18%) for the first passage. The tumor taking rates were higher in the second and third passages (80–100%). Paclitaxel and gemcitatbine produced tumor growth inhibition rates of 50–53% regardless of the EGFR and K-ras mutation status. While erlotinib demonstrated a significant antitumor activity only in the tumors bearing EGFR mutation with wild-type K-ras, which were consistent with their clinical findings. The tumor xenografts’ architecture, the cell and histopathological morphology from the three generations mirrored the original patient cancers. Conclusions: These results suggest that human primary tumor xenograft models provide a unique renewable source of tumor material for test of novel anticancer agents. They may predict more relevant clinical response rates and higher correlation with clinical findings than use of xenograft models established from long-term cultured cancer cell lines, especially for test of target-oriented therapeutics in new drugs development programs. No significant financial relationships to disclose.