Effect of alpha interferon on growth of leukemic and normal hematopoietic progenitors. Synergism with H2 histamine receptor antagonists

We studied whether the histamine H2 receptor antagonist, cimetidine, potentiates antiproliferative effects of recombinant alpha interferon (IFNα) on in vitro clonal growth of certain normal and malignant hematopoietic cells. Cimetidine alone, at therapeutic serum concentrations, was not inhibitory to the cells studied. IFNα alone inhibited the growth of HL-60 leukemic cells only at concentrations >1000 U/ml, whereas with cimetidine, inhibition was seen at >1 U/ml of IFNα. The enhancing effect of cimetidine on IFNα inhibition of clonal growth was neutralized by histamine and was not seen with histamine H1 receptor antagonist. In HL-60 cells, cimetidine also increased the enzymatic activity of (2'-5')-oligoadenylate synthetase, induced by IFNα. The combination of cimetidine and IFNα had a synergistic inhibitory effect on the growth of leukemic granulocyte-macrophage colony-forming units (CFU-GM) from chronic myeloid leukemia patients, normal CFU-GM, and normal erythroid burst-forming unit (BFU-E) progenitors. These data suggest that cimetidine may play a role in overcoming resistance to IFNα therapy in leukemia, but may also increase IFNα hematopoietic toxicity.