Enhancement of the antiproliferative activity of human interferon by polyamine depletion

Recombinant leukocyte type A human interferon and human lymphoblastoid interferon in combination with alpha-difluoromethylornithine (DFMO), an inhibitor of polyamine biosynthesis, have synergistic antiproliferative activity against colony formation in vitro by human tumor cells differing greater than 1000-fold in their intrinsic sensitivity to inhibitory effects of interferon. Interferon and DFMO in combination with doxorubicin have greater antiproliferative activity than is expected on the basis of additive effects based on the activity of doxorubicin alone and the synergistic activity of interferon plus DFMO. The addition of the polyamine putrescine to the cell cultures eliminates the synergistic interactions of interferon and DFMO and does not inhibit the activity of interferon itself. Aspirin and indomethacin at concentrations in vitro greater than those required for anti-inflammatory activity in vivo did not inhibit the antiproliferative activity of interferon alone and did not inhibit the synergistic activity of the combination of interferon and DFMO. Combination regimens including interferon and DFMO merit clinical evaluation for therapeutic activity against advanced cancers. Nonsteroidal anti-inflammatory agents should be studied for their ability to ameliorate symptomatic toxicity from interferon.