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 (IFN alpha) 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. IFN alpha alone inhibited the growth of HL-60 leukemic cells only at concentrations greater than 1000 U/ml, whereas with cimetidine, inhibition was seen at greater than 1 U/ml of IFN alpha. The enhancing effect of cimetidine on IFN alpha 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 IFN alpha. The combination of cimetidine and IFN alpha 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 IFN alpha therapy in leukemia, but may also increase IFN alpha hematopoietic toxicity.
Douer
D
D
Institute of Hematology, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
Kneller
A
A
Ben-Bassat
I
I
Chitayat
S D
SD
Shaked
N
N
Salzberg
S
S
Ramot
B
B
D015088:2',5'-Oligoadenylate Synthetase / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002927:Cimetidine / Q000494:pharmacology*; D003114:Colony-Forming Units Assay; D004357:Drug Synergism; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D007938:Leukemia / Q000097:blood / Q000473:pathology*; D011994:Recombinant Proteins; D013234:Stem Cells / Q000187:drug effects* / Q000201:enzymology
D007370:Interferon Type I; D011994:Recombinant Proteins; D002927:Cimetidine; D015088:2',5'-Oligoadenylate Synthetase