Biology and therapy of human small cell lung cancer (SCLC) in novel orthotopic nude mouse models

5136 SCLC is one of the most aggressive phenotypes of human lung cancer and conveys a poor prognosis due to the limited efficacy of existing treatment strategies. To provide clinically relevant strategies for studying new therapeutics and tumor biology, we developed three orthotopic models of human SCLC in nude mice. Three different human SCLC cell lines (H69A, a variant of the NCI-H69 cell line selected for invasiveness in vitro on semisolid agarose; NCI-H187; and NCI-N417) were studied. Tumor cells (1.5 x 106 cells in growth factor reduced Matrigel) were injected into the left lung of anesthetized nude mice. Tumors developed within 8 to 12 weeks and new cell lines were established from the lung tumors (H69ALu, H187Lu, and N417Lu) to select for a reproducible growth pattern for the orthotopic tumors and to minimize variation of tumor size. For each model, tumors started as a solitary mass in the left lung tumor that then spread to mediastinal and axillary lymph nodes, and to the right lung in a pattern similar to that observed in the clinic. N417Lu and H187Lu formed a 100 mm3 left lung mass within 30-40 days of injection, and mice were moribund within 50 to 60 days of injection. H69ALu tumors reached a volume of 100 mm3 within 60 days of injection and mice became moribund within 4 to 6 months. All tumors larger than 100mm3 expressed the proangiogenic factors bFGF and IL-8 (at the tumor periphery), and VEGF/VPF (tumor center and periphery).To compare the efficacy of different chemotherapeutic agents in each of our models, groups of mice (n = 5) were randomized to weekly i.p. treatment with saline (control), 6 mg/kg/mouse of cisplatin (CDDP), 50 mg/kg/mouse of paclitaxel, 125 mg/kg/mouse of irinotecan (CPT-11), or 40 mg/kg/mouse of etoposide. Therapy was initiated on day 10 (H187Lu and N417Lu) or day 20 (H69ALu) after tumor injection coincident with the formation of microscopic lesions. Therapy was well tolerated and mice were killed after five (H187Lu and N417Lu) or seven (H69ALu) weeks of therapy. Tumor burden was assessed by lung and tumor weight (g) and primary tumor volume (mm3). CPT-11 significantly inhibited the growth and progression of N417Lu tumors as compared to control (lung and tumor weight 0.23 ± 0.01 vs. 0.62 ± 0.15, p = 0.02; tumor volume 0.3 ± 0.1 vs. 364 ± 156, p = 0.03) and CDDP significantly inhibited the growth and progression of H69ALu tumors as compared to control (tumor volume 0.3 ± 0.1 vs. 100 ± 0.01, p = 0.04). The development of our orthotopic models of SCLC provides a better understanding the biology of this disease and will enable evaluation of novel therapeutic strategies (supported by a grant from the Department of Defense (DAMD 17-02-1-0706 to W.K.H.).