The overall objective of this proposal is to determine if a new class of compounds, the bis(ethyl)polyamines, has potential as antineoplastic agents for the treatment of lung cancer. Therefore, we will examine the role which the polyamine catabolic enzyme spermidine/spermine N1- acetyltransferase (SSAT) plays in determining the therapeutic response of human lung cancers to the bis(ethyl)polyamine analogues. The proposed studies are designed to extend preliminary results which demonstrate a phenotype specific cytotoxic response to the polyamine analogue N1,N12- bis(ethyl)spermine (BESpm). Specifically several human non-small cell lines were found to respond in rapid cytotoxic manner to treatment with BESpm, whereas human small cell lines are generally unaffected. the cytotoxic response of the non-small cell lines is accompanied by a tremendous increase in SSAT activity, in contrast to the small cell lines, where no such increase is observed. By exploiting the unique advantages of the Core Tissue Resource of the current SPORE proposal, the SSAT response of patient lung tumor tissue to bis(ethyl)polyamine exposure will be examined. The specific studies are designed to: 1) extend results which indicate the induction of SSAT has a role in determining the sensitivity of lung cancer cells to the polyamine analogues, 2) examine the response of normal bronchial epithelial cells to bis(ethyl)polyamine treatment to determine if a basis for tumor selectivity exists, 3) examine freshly derived tumor tissue to determine if the behavior of the human lung cancer lines are predictive of the actual clinical situation, 4) determine if SSAT activity can be used as a prognostic indicator of sensitivity to the bis(ethyl)polyamines, and 5) examine tumor tissue exposed to the bis(ethyl)polyamine BENSpm in clinical trial, to assess the biochemical effects of such treatment (see Project 7B).
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