Validation of an orthotopic model of human lung cancer with regional and systemic metastases

BACKGROUND: We developed an orthotopic model of human lung cancer that exhibits highly predictable regional and systemic metastases. This study examines the response of the model when treated with conventional and experimental chemotherapy. METHODS: NCI-H460 tumor fragments were implanted into the right caudal lung lobe of a nude rat. Treatment commenced 2 weeks later. We assessed response by comparing primary tumor and mediastinal lymph node weights, total body weight, and length of survival with untreated, tumor-bearing control animals. We also calculated the incidence of metastasis to kidney, bone, brain, and contralateral lung in treated versus untreated animals. RESULTS: Mitomycin and cisplatin showed broad activity against primary and metastatic disease. The matrix metalloproteinase inhibitor batimastat, low-dose cisplatin, and mitomycin significantly prolonged survival. High-dose cisplatin caused renal toxicity that shortened survival. Brain metastases did not respond to mitomycin, consistent with its poor blood-brain barrier penetration. CONCLUSIONS: Responses were similar to NCI-H460 in vitro data and consistent with clinical experience for these drugs. Drug-related toxicities similar to those seen in clinical practice were detected.