Biochemical effects of human alpha interferon in combination with alpha-difluoromethylornithine on human lymphoblastoid (DAUDI) cells in culture.
DFMO and IFN have both been shown to suppress the intracellular activity of ornithine decarboxylase in rapidly proliferating tissues. In addition, both agents demonstrate antiproliferative activity against human lymphoblastoid (Daudi) cells in culture. Treatment of log-phase Daudi cells with doses of 6 U/ml of IFN or 1 mM DFMO resulted in a 50% reduction of cell number 72 h after drug addition. Combination of IFN with DFMO against DAUDI cells using the isobologram method showed that the two demonstrate true antiproliferative synergy. Analysis of 2',5'-oligoadenylate synthetase (2,5A) activity in treated cells showed that both IFN alone and IFN/DFMO combination result in equivalent 2,5A induction (1800 mmol/mg/20 h) compared to control (300 mmol/mg/20 h). While 2,5A activity decreased by 50% at 48 h in cells after treatment with IFN alone, the IFN/DFMO combination remained elevated (1700 mmol/mg/20 h). Phosphodiesterase (PdE) activity in these cells showed no substantial changes with IFN, DFMO, or IFN/DFMO treatment over 72 h compared to control values. In contrast, the activity of the 68-kDa interferon induced protein kinase (PK) in IFN/DFMO-treated cells was 1.6-fold greater at 48 and 72 h than that found for IFN alone. These studies demonstrate that the synergistic antiproliferative activity of IFN/DFMO combination may be due, in part, to modification of the activity of IFN-inducible enzymes.
Rosenblum
M G
MG
Department of Clinical Immunology and Biological Therapy, University of Texas System, M.D. Anderson Cancer Center, Houston 77030.
D015088:2',5'-Oligoadenylate Synthetase / Q000187:drug effects / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D000518:Eflornithine / Q000494:pharmacology*; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D007945:Leukemia, Lymphoid / Q000628:therapy*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects / Q000378:metabolism; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects
D007370:Interferon Type I; D011494:Protein Kinases; D015088:2',5'-Oligoadenylate Synthetase; D010727:Phosphoric Diester Hydrolases; D000518:Eflornithine