Steady-State Messenger RNA and Activity Correlates with Sensitivity to 7V, A12-Bis(ethyl)spermine in Human Cell Lines Representing the Major Forms of Lung Cancer

Our previous results from a limited number of cell lines have sug-gested that the bis(ethyl)polyamine analogues exert a phenotype-spe-cific response in human lung cancer cells. In the present study, we have extended this work to analyze the response of the 4 major forms of human lung cancer to the polyamine analogue N W -bis(ethySpermine (BESpm). The results suggest that non-small cell phenotypes are much more sensitive to the cytotoxic effects of BESpm than the small cell lung carcinoma phenotype. Further, there appears to be a positive association between the level of induction of the polyamine catabolic enzyme spermidine/spermine N -acetyltransferase (SSAT) in response to the analogue and the kinetic response of cells. Specifically, cells in which SSAT activity is highly induced by BESpm are killed by the compound. Although induction of SSAT appears to occur at both the level of increased steady-state mRNA and enzyme activity, SSAT activity appears to be a better indicator of cell sensitivity to BESpm than SSAT mRNA levels. These results have significance both for the potential use of polyamine analogues in treating specific forms of human lung cancer and for understanding the regulation of SSAT at the molecular level. induction of this enzyme activity by BESpm is accompanied by a marked increase in SSAT protein and increased mRNA levels (13, 14). In order to further understand the underlying mechanisms of BESpm cytotoxicity and its relationship to the induction of SSAT, we now compare the growth and survival of multiple human lung cancer phenotypes with their ability to induce SSAT at the enzyme and steady-state mRNA levels. The polyamine analogue BESpm has been used to treat 8 different human lung cancer cell lines representing the 4 major types of human lung cancers (15-17). The findings are consistent with the hypotheses that the sensitivity to BESpm is phenotype dependent and that this sensitivity correlates with the level of induction of SSAT. An understanding of the dynamics of the cellular responses to JV,JV-bis(ethyl)polyamine analogues may enhance our ability to design and use such analogues as effective antineoplastic agents.