PATIENT-LIKE NUDE-MOUSE METASTATIC MODEL OF ADVANCED HUMAN PLEURAL CANCER

Pleural cancer in humans is a frequently occuring tumor. Recently, clinical trials have suggested that chemotherapy and immunotherapy administered intrapleurally may elicit responses in early-stage diseases. However, at radiological and pleural endoscopic evaluation, most of the patients are found to have a visceral pleural involvement that is generally refractory to therapy and leads to a poor prognosis. The goal of this study was to construct a nude mouse model of human parietal- and visceral-pleural cancer that could reflect the clinical picture for this disease. The model could then be useful for drug discovery for pleural cancer. A well-differentiated human lung adenocarcinoma was used as intact tissue for implantation. Ten mice underwent parietal-pleural implantation and ten mice visceral-pleural implantation via a novel thoracotomy procedure we have developed. Symptoms of tumor growth were determined from weight loss, respiratory distress, or debilitation. Actual tumor growth and spread were measured at autopsy. The mouse survival curves of each group were estimated by the Kaplan-Meier method and the difference of the median survival times was assessed by the Log-rank test. The slopes of mean-mouse weight curves were compared using a standard two-sample t-test. A 100% take rate was achieved in constructing the pleural cancer models. Tumor growth was initially assessed by symptomatology and survival: the median survival time was, respectively, 27.9 days and 31 days for visceral-pleural and parietal-pleural implanted groups (P < 0.05). The comparison between the slopes of the mean weight curves of corresponding groups demonstrated that visceral-pleural implanted animals lost significantly more weight than the parietal-pleural implanted animals (P < .001). Both in the visceral- and parietal-pleural implanted groups, post-mortem analysis revealed that tumor grew in all mice demonstrating local and regional spread mimicking clinical features. However, mediastinal lymph node metastases were observed only in mice with visceral pleural implantation. Patient-like models of human parietal-pleural and visceral-pleural cancer were constructed in nude mice using histologically intact human specimens. Tumor symptoms, growth, and spread as well as survival indicated that the parietal-pleural and visceral-pleural models represent, respectively, early- and advanced-stage disease. These ''patient-like'' nude mouse models of pleural cancer now allow a rational basis for further studies of pleural cancer biology,pathophysiology, and therapeutics. (C) 1994 Wiley-Liss, Inc.