Antiproliferative effects of interferon gamma in combination with alpha-difluoromethylornithine on human carcinoma cell cultures

Abstract

The antiproliferative effects of human recombinant interferon gamma (IFN gamma) in combination with alpha-difluoromethylornithine (DFMO) or as single agents were assessed on human cell cultures derived from carcinomas of the breast (MCF-7), the ovary (EFO-27) or the kidneys (EGI-4). Results were obtained in proliferation assays by direct cell counting. The cell lines differed considerably in their sensitivities to the antiproliferative effect of IFN gamma as compared by the 50% inhibition doses of the growth (ID50). In contrast to the findings with IFN gamma, similar antiproliferative effects resulted from the application of comparable doses of DFMO. While IFN gamma induced cytotoxic effects in EGI-4 cells, DFMO produced only cytostatic actions in the cell lines analyzed. Synergistic growth inhibition resulted from the combined application of IFN gamma and DFMO in EFO-27 cell cultures. This finding was most pronounced after treatment with IFN gamma or DFMO doses below the respective ID50 values. However, antagonistic effects occurred in cells of the line EGI-4 after DFMO had been combined with IFN gamma at concentrations below the cytotoxic dose range. Within the sensitivity of our proliferation assay, no synergistic interactions were found in MCF-7 cell cultures. In the cell lines tested, no relation between the sensitivity for the single agents and the effectivity of the drug combination was identified. Despite promising synergistic effects in the moderately IFN gamma-sensitive ovarian carcinoma cell line EFO-27, the efficacy of the IFN gamma/DFMO combination was restrained by possible antagonistic effects as demonstrated in the highly IFN gamma-sensitive EGI-4 renal carcinoma cell cultures. We conclude that the differential interaction patterns in the cell cultures analyzed preclude general suggestions for clinical studies using IFN gamma and DFMO.