If anticancer agents can be directed or targeted to lung cancer, the efficacy of these agents may be improved while dose limiting toxicities and non-specific uptake substantially reduced. We have developed a surgically created, anatomical method of isolating and perfusing the lung in vivo. The methodology involves techniques and instrumentation routinely used in the performance of cardiopulmonary bypass for cardiac surgery. The rationale is to deliver these anticancer agents to local-regional lung cancer in an effort to maximize tumoricidal activity while limiting toxicity. To fully exploit this system we will develop a small animal tumor- bearing lung perfusion model using the recently described technique for growing human lung cancer cell lines orthotopically in the lungs of nude rats. These tumor-bearing lungs will then be subjected to an acute perfusion using the long established rat lung perfusion methods. Anticancer agents including chemotherapy, radiolabeled monoclonal antibodies, and hyperthermia will be introduced into the perfusion. Tumor cell kill will be quantitated using three assay methods: nitro-blue tetrazolium, colony- forming, and flow cytometry. Normal lung toxicity will be measured by physiological parameters of lung injury, including gas exchange, weight, hemodynamics, and endothelial cell function studies. A series of acute normal dog in vivo lung perfusions will be performed to critically assess certain aspects of the system, including; perfusate composition, perfusate distribution, and systemic/pulmonary crossover. The ultimate goal is to design and carry out survival studies with long-term follow up of in vivo lung perfusion with selected anticancer agents in naturally occurring lung tumor-bearing dogs.
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