Growth-Inhibitory Effects of dl-α-Difluoromethylornithine in the Spectrum of Human Lung Carcinoma Cells in Culture

DL-α-Difluoromethyl ornithine (DFMO) is a new and specific inhibitor of the first step in polyamine biosynthesis. We recently reported that DFMO profoundly diminishes cell survival in a single culture line of human small-cell lung carcinoma (SCC). In the present study, we have extended this work to ascertain: (a) the effects of DFMO on the spectrum of cell growth for SCC in culture; and (b) how the response of SCC cells to DFMO compares to that for the other three major types of human lung cancer cells. SCC cells were found to have a unique response to DFMO among the types of lung cancer; exposure of eight separate lines to the drug, during the exponential growth phase, produced an initial inhibition of cell increase followed by a progressive and complete loss of cells from the cultures. There was a heterogeneous response pattern among the SCC lines in that the time of onset for cell loss ranged from 4 days to 4 weeks. In marked contrast to SCC, two lines of human lung adenocarcinoma, one of squamous cell carcinoma and one of large cell undifferentiated carcinoma, had a more usual response to inhibition of polyamine biosynthesis. Despite a cessation of cell proliferation during DFMO treatment, no cell loss ensued over periods up to 8 weeks in these cultures. The above results with SCC and non-SCC cells suggested that the former could not live well in culture as a resting, nonproliferative cell. We further tested this hypothesis by exposing to DFMO stationary-phase 4-week-old aggregates of cultured SCC cells, in which cell proliferation and cell loss are balanced; within 2 weeks, the profound loss of cells was again manifest. We conclude that: (a) in culture, SCC cells, among human lung cancer types, have a unique sensitivity to inhibition of polyamine biosynthesis; (b) the heterogeneity for timing of SCC response to DFMO may have to be taken into account when investigating the therapeutic potential of the drug, DFMO; and (c) the biological differences between SCC and non-SCC cells in response to DFMO may provide a model system for establishing further the functional role of the polyamines.