All of the standard anticancer agents, including many of the chemotherapeutic drugs, radiation, and hyperthermia are tumoricidal against lung cancer if given in adequate concentrations under the appropriate conditions. Physical limitations and normal tissue toxicity often prevent the beneficial effects of these agents to be maximally exploited. Lung cancer is often said to be resistant to these anticancer agents when in actuality the problem is inefficient or inappropriate delivery to the tumor. This NCDDG for Lung Cancer will attempt to optimize targeting of these agents to the tumor by implementing two novel delivery systems; in vivo lung perfusion and lung cancer specific monoclonal antibodies. Both of these systems have undergone extensive laboratory investigation and both are now in early clinical trials. We will use these targeting methods to evaluate the anticancer agents in two newly available animal models. A small animal lung perfusion model in nude rats bearing orthotopically implant human lung cancer as recently described by McLemore will be our initial screening method. Tumor viability will be quantitated following the acute perfusion by the nitro-blue tetrazolium assay, the colony-forming assay, and by flowing cytometry. Promising formulations of an agent or a combination of agents will then be scrutinized by in vivo dog lung perfusions in dogs with naturally occurring cancers in the lung. Normal tissue toxicity of the agents will initially be evaluated by comprehensive pulmonary physiological measurements in ex vivo lobe perfusions. The information gained will then be applied to the in vivo dog lung perfusions where appropriate radiological and physiological studies will be performed at predetermined intervals after perfusion to assess possible long-term injury patterns and tumor response. Thus, the specific aims of this project are: 1) to develop tumor-bearing small and large animal models appropriate for evaluating anticancer agents specific to lung cancer; 2) to improve and refine two novel delivery systems targeted at lung cancer; 3) to combine the delivery systems with the animal tumor models to optimize and objectively evaluate the anticancer agents; 4) to study the effects of these therapies on normal lung and attempt to manipulate studies, clinical trials utilizing either the specific agents, the delivery systems, or combinations of both should be reasonably implemented.
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