Relapsing small cell lung cancer (SCLC) is an incurable condition. To develop more effective therapeutic approaches for this condition, clinically relevant SCLC animal models are needed. We have developed in vivo SCLC models that have the potential of fitting this important need. Methods: Human SCLC cell lines were inoculated into nude mice subcutaneously (sc) or intravenously (iv). When the tumors were established (5~7 mm), mice were treated with cisplatin using an optimized schedule until the tumors were invisible or reduced in size by >90%. Tumor regrew in >80 % of mice about 5-7 weeks later. Relapsing tumors were resected and reimplanted in tumor-naïve mice to develop chemoresistant in vivo models of SCLC. Results: Adherent cells from cultures of cell lines H69 AR and H446 grow rapidly when inoculated sc, but induce a low number of lung metastases after iv inoculation. Cells in suspension from cultures of cell lines H69, H82, H345 and H660 grow rapidly when inoculated sc and also induce a large number of lung metastases in close to 100% of mice after iv inoculation. Expression of the anti-apoptotic genes of the Bcl-2 family is inversely related to initial in vivo cisplatin sensitivity. Most tumors regrow upon discontinuation of initial cisplatin therapy. All relapsed tumors are highly resistant to cisplatin therapy (average resistance index increased >2.4-fold). Relapsed tumors can be implanted to other tumor-naïve nude mice with a 100% taking rate. Detailed molecular characterization of these resistant tumor models is ongoing and will be presented. Summary: The tumor models develop retain the basic characteristics of human SCLC: high hematogenous metastatic potential, high responsiveness to initial chemotherapy, high relapsing potential, and early development of resistance to chemotherapy. The models are currently been used to test new therapeutic modalities for this disease.

Acknowledgement: Supported by NIH grant 1 R21 CA104297 to Y Zou.

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