Thiorphan stimulates clonal growth of GM-CFU in short term cultures of bone marrow from a healthy donor and from patients with non-Hodgkin lymphoma

Abstract

Thiorphan, a specific inhibitor of membrane neutral endopeptidase (NEP, EC 3.4.24.11) also known as the common acute lymphoblastic leukemia antigen (CALLA, CD10) was added into short-term clonal cultures of the buffy coat concentrates of human bone marrow obtained from a healthy donor (six experiments) and from ten patients with non-Hodgkin lymphoma (NHL) (eight in complete remission, one in partial remission and one in relapse). Thiorphan concentrations ranged from 10(-5) to 10(-13) M. Nanomolar and higher concentrations of the drug mildly stimulated the granulocyte-macrophage colony-forming unit (GM-CFU) counts in the cultures of normal bone marrow, reaching the significance at 10(-7) M. Meaningful alterations of the GM-CFU counts were noted in 31 of 79 thiorphan-treated cultures of NHL bone marrow (39%). In those cultures the stimulatory effects (33%) outnumbered the inhibitory ones (6%). The stimulatory effects occurred mainly in the bone marrow samples of the patients with highly malignant NHL. The observations are compatible with the idea that the membrane endopeptidase (CALLA, CD10) participates in processes controlling the proliferation and differentiation of hematopoetic cells by cleaving the neuropeptides and related hemoregulatory peptides.