Takeshi Isobe, MD, PhD, Amir Onn, MD, Daniel Morgensztern, MD, Jörg J

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Evaluation of Novel Orthotopic Nude Mouse Models for Human Small-Cell Lung Cancer Takeshi Isobe, MD, PhD, Amir Onn, MD, Daniel Morgensztern, MD, Jörg J. Jacoby, PhD, Wenjuan Wu, PhD, Tomoaki Shintani, MD, Satoshi Itasaka, MD, Keiko Shibuya, MD, Peter J. Koo, PhD, Michael S. O'Reilly, MD, Roy S. Herbst, MD, PhD Journal of Thoracic Oncology Volume 8, Issue 2, Pages 140-146 (February 2013) DOI: 10.1097/JTO.0b013e3182725ff9 Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Tumor growth and metastasis after intrapulmonary injection of N417Lu cells. A, Histopathologic findings of a pulmonary nodule. Solitary nodules surrounded by normal lung developed 10 days after injection of tumor cells; tumor size increased with time. B, Macroscopic findings of orthotopic lung tumor on day 20 after intrapulmonary implantation. C, Histopathologic findings of contralateral lung metastasis on day 50 after intrapulmonary implantation. D, Macroscopic findings of lung tumor (arrow) and mediastinal lymph node (arrowhead) on day 50. Journal of Thoracic Oncology 2013 8, 140-146DOI: (10.1097/JTO.0b013e3182725ff9) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Direct macroscopic view of GFP-transfected human small-cell lung cancer (SCLC) cells with orthotopic tumor and micrometastasis. A, Direct image of orthotopic human SCLC cells (H187Lu) 15 days after injection. B, Micrometastasis in the mediastinal (paraesophageal) lymph node 15 days after injection. C, micrometastasis in the right axillary lymph node 50 days after injection. D, Micrometastasis in the liver 50 days after injection. Journal of Thoracic Oncology 2013 8, 140-146DOI: (10.1097/JTO.0b013e3182725ff9) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 In vivo growth curve of N417Lu (▄), H187Lu (▴), and H69ALu (• ) cell lines injected into the left lung. Five mice per group were orthotopically implanted with human small-cell lung cancer cells as described in Materials and Methods. Vertical bars represent the standard error of the mean. Note that N417Lu and H187Lu cell lines had a faster growth rate than the H69ALu cell line (p < 0.01). Journal of Thoracic Oncology 2013 8, 140-146DOI: (10.1097/JTO.0b013e3182725ff9) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Antitumor effects of irinotecan, paclitaxel, cisplatin, and etoposide as single agents administrated to mice bearing orthotopic lung tumors. A–E, cross-sectional gross images of an H69ALu tumor treated with vehicle, irinotecan, paclitaxel, cisplatin, or etoposide. F–J, macroscopic findings of an H69ALu tumor treated with vehicle, irinotecan, paclitaxel, cisplatin, or etoposide. Arrows indicate tumor borders. Journal of Thoracic Oncology 2013 8, 140-146DOI: (10.1097/JTO.0b013e3182725ff9) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 Therapeutic effects of irinotecan in the N417Lu orthotopic lung tumor model. Mice were injected intraperitoneally with 15-mg/kg irinotecan on days 14, 21, 28, 35, 42, and 49 after the implantation of 1.5 × 106 N417Lu tumor cells into the left lung. Irinotecan significantly improved survival over control (p = 0.018). The survival data was compared using the log-rank test. Journal of Thoracic Oncology 2013 8, 140-146DOI: (10.1097/JTO.0b013e3182725ff9) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions