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Additive and Differential Biological Activity of -Interferon A, Difluoromethylornithine, and Their Combination on Established Human Lung Cancer Cell Lines

NCI-Navy Medical Oncology Branch and National Naval Medical Center, Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20814

The effect of human recombinant leukocyte interferon A (IFN-A) and DL--difluoromethylornithine (DFMO) as single drugs and in combination on the in vitro growth, cell cycle distribution, activity of the enzyme L-dopa decarboxylase, and expression of the c-myc and N-myc oncogenes was studied in human lung cancer cell lines. In vitro growth activities were tested in concentrations ranging from 10 to 50,000 IU/ml for IFN-A and from 0.1 to 10 mM for DFMO by means of the soft agarose clonogenic assay using continuous drug exposure. Ten well established small cell lung cancer (SCLC) cell lines including five cell lines of the classic and five of the variant phenotype, two cell lines derived from adenocarcinoma of the lung, and one large cell lung cancer cell line were included in the study. We found that IFN-A inhibited the growth only of the variant phenotype of SCLC with an approximate drug concentration yielding a 50% inhibition of colony growth of 1000 IU/ml. None of the SCLC classic cell lines was inhibited significantly. The growth inhibition of IFN-A correlated with the proliferation rate of the tumor. IFN-A inhibited one of two adenocarcinoma cell lines and 0 of 1 large cell lung cancer cell line. DFMO inhibited the colony formation of 10 of 10 SCLC cell lines, 2 of 2 adenocarcinoma cell lines, and 0 of 1 large cell lung cancer cell line with a drug concentration yielding a 50% inhibition of colony growth of 1 mM. No difference between the classic and variant phenotypes of SCLC was found. The combination of IFN-A and DFMO resulted in an additive cytostatic effect in all cell lines tested. The same result, i.e., an additive cytostatic effect, was obtained for two SCLC cell lines that were tested in liquid culture. Neither single drugs nor their combination led to an accumulation of cells in a particular phase of the cell cycle nor did it affect the activity of the SCLC classic marker enzyme L-dopa decarboxylase. In addition, IFN-A, DFMO, and their combination did not affect the expression of the c-myc and N-myc oncogenes in cell lines NCI-N417 and NCI-H526, respectively, following 4, 24, and 72 h of continuous drug exposure. We conclude from these studies that (a) the growth inhibiting activity of IFN-A on SCLC is not directly related to the expression of the myc oncogenes but is the result of an interaction with an unknown mechanism that is responsible for high tumor growth rate; (b) depletion of polyamines in cells does not affect the expression of the myc oncogenes; and (c) IFN-A and DFMO have and additive cytostatic effect in human lung cancer. Nude mouse studies will be necessary to confirm these results before entering into clinical trials. One should expect that only patients suffering from the variant phenotype of SCLC may benefit from a treatment regimen that combines both drugs, IFNs and DFMO.

¹ Present address: Zentrum fuer Innere Medizin, Abt. Haematologie/Onkologie, Baldingerstrasse, 3550 Marburg, Federal Republic of Germany. To whom requests for reprints should be addressed.

² Present address: Mater Misericordiae Hospital, Eccles Street, Dublin 7, Ireland.

Received 12/ 4/85. Revised 3/31/86. Accepted 4/ 3/86.