Toxin Gene-Mediated Growth Inhibition of Lung Adenocarcinoma in an Animal Model of Pleural Malignancy

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Abstract
Transduction of malignant cells with toxin genes provides a novel strategy by which to promote tumor cell destruction. Whereas the capacity of the toxin gene/prodrug combination cytosine deaminase/fluorocytosine to inhibit growth of human metastatic pulmonary adenocarcinoma cell lines in vitro is established, the in vivo efficacy of this binary system has not yet been determined. For the development of toxin gene therapy for the treatment of lung adenocarcinoma metastatic to the pleural space, a reliable, disease-specific model is required. The serosa of the rat small intestine resembles the basal lamina of the pleura and provides the basis for a more convenient model than direct injection of tumor into the pleural space. Adenocarcinoma cells are innoculated into everted denuded rat intestine configured as a sac. Immunocytochemical and histological analyses show rapid cell growth with characteristics that mimic nodular metastatic intrapleural disease. In the context of this model, systemically delivered fluorocytosine significantly inhibits the growth of cytosine deaminase-expressing human lung adenocarcinoma cells. The dosing schedule required 30 days; neither addition of an enzyme inhibitor that increases the half-life of fluorocytosine nor intralumenal drug delivery is effective in shortening (to 15 days) the protocol. We conclude that CD continues to hold promise as a toxin gene for lung adenocarcinoma gene therapy, and that prolonged prodrug administration may be required for maximum efficacy. In our endeavor to develop toxin gene therapy as an adjuvant treatment for metastatic lung adenocarcinoma, a study determining the in vivo efficacy of CD at inhibiting tumor growth is required. Previously, in vitro analysis had indicated that CD was an efficacious toxin gene in model cell lines, and that in vivo studies were warranted. Unfortunately, the lack of an appropriate animal model of pleural malignancy hindered further investigations. Therefore, we developed a versatile and quantitative animal model that mimicks the pleural space. This study describes the pleural model methodology and biology and the ability of the prodrug FC to inhibit the in vivo growth of human lung adenocarcinoma in the presence of CD.