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Differential Response to Treatment with the Bis(ethyl)polyamine Analogues between Human Small Cell Lung Carcinoma and Undifferentiated Large Cell Lung Carcinoma in Culture¹

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

We have compared the effects of treatment with each of three bis(ethyl)polyamine analogues on a human small cell lung carcinoma (SCLC) line, NCI H82, and a non-small cell line, NCI H157, an undifferentiated large cell lung carcinoma. The bis(ethyl)polyamines have been shown to interfere with polyamine metabolism, presumably by regulation of the polyamine biosynthetic pathway in a manner similar to the natural polyamines, in contrast to direct inhibition of specific enzymes, such as ornithine decarboxylase. Each of these compounds was found to be relatively inactive in reducing growth rate, polyamine levels, or polyamine biosynthetic enzyme activity in the SCLC cells, a line which we have previously shown to be particularly sensitive to inhibition of polyamine biosynthesis by the direct ornithine decarboxylase inhibitor difluoromethylornithine. By contrast, each of the bis(ethyl)polyamines tested was found to be markedly cytotoxic (at concentrations of only 10 µM) to the non-SCLC line, NCI H157. Interestingly, the non-SCLC line has previously been demonstrated to be resistant to polyamine depletion by difluoromethylornithine. For each bis(ethyl)polyamine, cytotoxicity was accompanied by nearly complete depletion of all intracellular polyamines and a decrease in ornithine decarboxylase activity to undetectable levels. The current study emphasizes the phenotypic variability which can exist in response to inhibitors of polyamine biosynthesis and suggests a class of agents which may have clinical utility against the treatment-resistant non-SCLC lung cancers.

¹ This work was supported by NIH Grants CA37606 and CA47492.

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

Received 8/15/88. Revised 10/21/88. Accepted 10/28/88.

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