Additive and differential biological activity of alpha-interferon A, difluoromethylornithine, and their combination on established human lung cancer cell lines.
The effect of human recombinant leukocyte interferon A (IFN-alpha A) and DL-alpha-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-alpha 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-alpha 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-alpha A correlated with the proliferation rate of the tumor. IFN-alpha 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-alpha 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-alpha 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.(ABSTRACT TRUNCATED AT 400 WORDS)
D000971:Antineoplastic Combined Chemotherapy Protocols; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D004296:Dopa Decarboxylase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000518:Eflornithine; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007370:Interferon Type I / Q000008:administration & dosage*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009952:Ornithine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D011519:Proto-Oncogenes; D011994:Recombinant Proteins / Q000008:administration & dosage*
D007370:Interferon Type I; D011994:Recombinant Proteins; D009952:Ornithine; D004296:Dopa Decarboxylase; D000518:Eflornithine