The major goal of this research program continues to be the laboratory examination of treatment strategies aimed at eradicating tumor cells growing in the lung. This proposal will investigate the role of extrinsic and intrinsic cellular factors and their interplay in determining the response of lung cancer cells to radiation, chemotherapeutic agents and nitroheterocyclic sensitizers used alone or in combination. Factors to be evaluated for their effect on treatment response include cellular thiol levels and potentially lethal damage repair (PLDR) capacity (intrinsic) as well as alterations in the environment (extrinsic). Experiments using human lung cancer models will evaluate means of manipulating these factors and assess whether such manipulations can yield a therapeutic gain. Emphasis will be placed on determining the role of PLDR in the response on lung tumor cells to radiation or chemotherapeutic agents. This will be done in cell lines grown both in tissue culture and as human tumor xenografts. Comparing the in vitro and in vivo PLDR capacity will allow the determination of the relevance of this factor in lung tumor therapy response and could have important implications on how best to attempt to predict clinical therapy outcome from laboratory investigations. Since cellular thiol concentrations can affect the efficacy of a variety of anticancer agents, it is also an objective to establish the importance of glutathione (GSH) levels as determinants of lung tumor cell response to radiation and/or drugs. These studies will not only determine the relationship between intrinsic GSH levels and therapeutic response but also will assess the role of GSH recovery in this process. Experiments aimed at manipulating the treatment response through the administration of the thiol depletor buthionine sulfoximine (BSO) also will be carried out. In particular, we will examine whether the use of BSO to affect GSH metabolism will lead to more effective potentiation of chemotherapeutic agents by hypoxic cell sensitizers or more efficacious drug-radiation interactions. The potential therapeutic benefit which may be achieved through these treatment strategies will be determined by also measuring effects in critical normal tissues (lung and bone marrow). These investigations should yield information which will improve our understanding of factors influencing cellular therapeutic response and may guide the efforts for the most effective use of combined modality therapies in lung cancer treatment.
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