Cancer chemotherapeutic agents such as bleomycin and the chloroethylnitrosureas (CENU) are associated with a high incidence of pulmonary toxicity. The lung injury and fibrosis induced by these drugs represents a major limiting factor in the therapeutic efficacy of these drugs in the treatment of cancer. Both bleomycin and CENU cause DNA damage by mechanisms including creation of apurinic/apyrimidinic (AP) sites, strand scissions and abnormal DNA adducts which lead to cell death. Pulmonary toxicity from cytotoxic drugs is typically associated with injury to the pulmonary capillary endothelium and the type I and type II alveolar epithelial cells. This project will focus on the role of specific DNA repair proteins in protecting lung cells from the DNA damaged caused by bleomycin or CENU and by hyperoxia, a condition associated with exacerbation of drug-induced lung disease. It is proposed that specific DNA repair proteins such as apurinic/apyrimidinic endonucleases (APE) will be protective from bleomycin-induce pulmonary toxicity and that methylguanine DNA methyltransferase (MGMT) will be protective from CENU induced toxicity. Both in vitro and in vivo studies are proposed. The hypothesis is: Augmentation of specific DNA repair proteins in lung cells will significantly reduce the toxicity of bleomycin or CENU.
Specific aims i nclude: 1) use viral or non-viral vectors to augment intracellular levels of DNA repair proteins in lung cell in vitro; 2) determine if augmentation of intracellular levels of DNA repair proteins in lung cells in vitro reduced lung cell toxicity from rugs (bleomycin, CENU, hyperoxia) in vitro; 3) determine if transgenic mice over-expressing DNA repair proteins in the lung are more resistant to toxicity from drugs (bleomycin, CENU, hyperoxia) in vivo; 4) determine if augmentation of DNA repair proteins in the lung by airway delivery of non-viral vectors reduces lung toxicity from drugs (bleomycin, CENU, hyperoxia) in vivo. If successful, this project will provide the experimental basis for protecting key lung progenitor cells form cytotoxic drug damage, thereby preserving the integrity of the alveolar capillary unit; and if injury occurs, permitting its cellular reconstitution by the protected lung cells undergoing normal compensatory replication and differentiation.
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