NOVEL INTRAPULMONARY MODEL FOR ORTHOTOPIC PROPAGATION OF HUMAN-LUNG CANCERS IN ATHYMIC NUDE-MICE

Abstract

A major impediment to the study of human lung cancer pathophysiology, as well as to the discovery and development of new specific antitumor agents for the treatment of lung cancer, has been the lack of appropriate experimental animal models. This paper describes a new model for the propagation of human lung tumor cells in the bronchioloalveolar regions of the right lungs of athymic NCr-nu/nu mice via an intrabronchial (i.b.) implantation procedure. Over 1000 i.b. implantations have been performed to date, each requiring 3 to 5 min for completion and having a surgery-related mortality of approximately 5%. The model was used successfully for the orthotopic propagation of four established human lung cancer cell lines including: an adenosquamous cell carcinoma (NCI-H125); an adenocarcinoma (A549); a large cell undifferentiated carcinoma (NCI-H460), and a bronchiolalveolar cell carcinoma (NCI-H358). When each of the four cell lines was implanted i.b. using a 1.0 .times. 106 tumor cell inoculum, 100 .+-. 0% (SD) tumor-related mortality was observed within 9 to 61 days. In contrast, when the conventional s.c. method for implantation was used at the same tumor cell inoculum, only minimal (2.5 .+-. 5%) tumor-related mortality was observed within 140 days (P < 0.001). Similarly, when a 1.0 .times. 105 or 1.0 .times. 104 cell inoculum was used, a dose-dependent, tumor-related mortality was observed when cells were implanted i.b. (56 .+-. 24% or 25 .+-. 17%) as compared with the s.c. method (5 .+-. 5.7% or 0.0 .+-. 0%) (P < 0.02 and P < 0.05, respectively). Most (> 90%) of the lung tumors propagated by i.b. implantation were localized to the right lung fields as documented by necropsy and/or high-resolution chest roentgenography techniques which were developed for these studies. The intrapulmonary model was also used for establishment and propagation of xenografts derived directly from enzymatically digested, fresh human lung tumor specimens obtained at the time of diagnostic thoracotomy and representing all four major lung cancer cell types as well as a bronchioloalveolar cell carcinoma. Approximately 35% (10 of 29) of the fresh primary human lung tumor specimens and 66% (2 of 3) of tumors metastatic to the lung were successfully propagated i.b. at a 1.0 .times. 106 tumor cell inoculum, whereas only 20% (1 of 5) of the specimens were successfully grown in vivo via the s.c. route from a 1.0 .times. 107 tumor cell inoculum. Our experience with this in vivo intrapulmoanry model for the orthotopic propagation of human lung tumor cells is consistent with the view that organ-specific in vivo implantation of human tumors facilitates optimal tumor growth. This new in vivo lung cancer model may substantially facilitate future studies of the biology and therapeutics of this catastrophic disease.