Thiorphan, an inhibitor of neutral endopeptidase/enkephalinase (CD10/CALLA) enhances cell proliferation in bone marrow cultures of patients with acute leukemia in remission.
Thiorphan, (DL-mercapto-2-benzylpropanoyl)-glycine is a potent and specific inhibitor of membrane metallo-endopeptidase (EC 3.4.24.11, CD10). We explored its effects in short-term clonal cultures of the bone marrow from 10 patients with acute leukemia in remission. The cell suspensions were incubated with thiorphan (10(-13) to 10(-5) M) and seeded for the granulocyte/macrophage-colony forming unit (GM-CFU) assay. In normal bone marrow samples the median seeding efficiency was 119 colonies and clusters per 10(5) cells and thiorphan caused slight stimulation of the clonal growth in concentrations above 10(-9) M. In the leukemic samples, the median seeding efficiency varied from 10 to 366 colonies and clusters per 10(5) seeded cells. Meaningful alterations of the clonal growth were noted in 32 out of 83 thiorphan-treated cultures (39%). In those 32 cultures the stimulatory effects outnumbered the inhibitory effects (24 versus 8). Thus, thiorphan stimulated the progenitor cell proliferation in bone marrow samples from the normal donor and from the patients with acute leukemia in remission. Thiorphan binding to CD10 might interfere with the processing of neuropeptide hemoregulatory factors and thus influence the progenitor cell proliferation.
Stanović
S
S
Department of Molecular Medicine, Ruder Bosković Institute, Zagreb, Croatia.
Boranić
M
M
Petrovecki
M
M
Batinić
D
D
Skodlar
J
J
Nemet
D
D
Labar
B
B
D000208:Acute Disease; D000754:Anemia, Refractory, with Excess of Blasts / Q000473:pathology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D007951:Leukemia, Myeloid / Q000473:pathology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology*; D012074:Remission Induction; D015244:Thiorphan / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay
D000806:Angiotensin-Converting Enzyme Inhibitors; D009363:Neoplasm Proteins; D011480:Protease Inhibitors; D015244:Thiorphan; D015260:Neprilysin