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Steady-State Messenger RNA and Activity Correlates with Sensitivity to N¹,N¹²-Bis(ethyl)spermine in Human Cell Lines Representing the Major Forms of Lung Cancer¹

The Oncology Center [R. A. C., A. R. M., L. X., J. S., P. C.], The Johns Hopkins University School of Medicine Oncology Center, Baltimore, Maryland 21231, and the Department of Medicinal Chemistry [R. J. B.], J. Hillis Miller Health Center, University of Florida, Gainesville, Florida 32610

Our previous results from a limited number of cell lines have suggested that the bis(ethyl)polyamine analogues exert a phenotype-specific 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 N¹·N¹²-bis(ethyl)spermine (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 N¹-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.

¹ This work was supported by NIH Grants CA37606, CA47492, CA51085, and CA51068, The McDonnell Foundation, and the Clayton Fund.

² To whom requests for reprints should be addressed, at The Johns Hopkins Oncology Center Laboratories, 424 North Bond Street, Baltimore, MD 21231.

Received 5/ 6/92. Accepted 7/22/92.

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