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

Pleural cancer in humans is a frequently occuring tumor. Recently, cli nical trials have suggested that chemotherapy and immunotherapy admini stered intrapleurally may elicit responses in early-stage diseases. Ho wever, at radiological and pleural endoscopic evaluation, most of the patients are found to have a visceral pleural involvement that is gene rally 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 t his disease. The model could then be useful for drug discovery for ple ural 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 t horacotomy procedure we have developed. Symptoms of tumor growth were determined from weight loss, respiratory distress, or debilitation. Ac tual tumor growth and spread were measured at autopsy. The mouse survi val curves of each group were estimated by the Kaplan-Meier method and the difference of the median survival times was assessed by the Log-r ank test. The slopes of mean-mouse weight curves were compared using a standard two-sample t-test. A 100% take rate was achieved in construc ting the pleural cancer models. Tumor growth was initially assessed by symptomatology and survival: the median survival time was, respective ly, 27.9 days and 31 days for visceral-pleural and parietal-pleural im planted groups (P < 0.05). The comparison between the slopes of the me an weight curves of corresponding groups demonstrated that visceral-pl eural implanted animals lost significantly more weight than the pariet al-pleural implanted animals (P < .001). Both in the visceral- and par ietal-pleural implanted groups, post-mortem analysis revealed that tum or grew in all mice demonstrating local and regional spread mimicking clinical features. However, mediastinal lymph node metastases were obs erved only in mice with visceral pleural implantation. Patient-like mo dels of human parietal-pleural and visceral-pleural cancer were constr ucted in nude mice using histologically intact human specimens. Tumor symptoms, growth, and spread as well as survival indicated that the pa rietal-pleural and visceral-pleural models represent, respectively, ea rly- and advanced-stage disease. These ''patient-like'' nude mouse mod els of pleural cancer now allow a rational basis for further studies o f pleural cancer biology,pathophysiology, and therapeutics. (C) 1994 W iley-Liss, Inc.