Difluoromethylornithine (DFMO), an enzyme activated irreversible inhibitor of ornithine decarboxylase (ODC), depletes intracellular putrescine, and spermidine (Spd), but not spermine, and generally leads to an inhibition of cell proliferation, without cell death, in both normal and neoplastic cells. This is the case with a culture line of human large cell undifferentiated lung cancer, NCI H157, which will survive indefinitely in DFMO containing medium and ultimately actually grows through the DFMO block. We now provide evidence that a Spd analogue, N1,N8-bis(ethyl)spermidine (BES) also suppresses ODC activity in H157 cells but leads not only to complete depletion of putrescine and Spd but also reduces intracellular spermine to 20–30% of control levels. This depletion of polyamines is accompanied by a rapid decrease in cell proliferation and ultimately cell death. The cell death resulting from BES treatment is in direct contrast to results obtained with DFMO and occurs at concentrations of less than 10 µm, whereas 5 mm DFMO is required to maintain growth inhibition in NCI H157. The observed suppression of ODC activity by BES is consistent with mechanisms by which Spd itself regulates ODC activity. Our data suggest that although both agents, DFMO and BES, interfere with polyamine metabolism, the differential sensitivities to these agents indicate susceptibility to polyamine depletion may be agent and cell type specific. Such differences may be related to the different requirement of individual cell types for polyamines and different regulatory events in polyamine biosynthesis. These differences may be exploitable in the treatment of neoplastic disease with polyamine analogues or inhibitors of polyamine biosynthesis.
This work was supported by NIH Grants CA37606, CA43280, CA09071, and AM27157.