Monocyte activation by an oral immunomodulator (bestatin) in lymphoma patients following autologous bone marrow transplantation.
Bestatin (ubenimex), an inhibitor of aminopeptidase, is an oral immunomodulator that binds to CD13 (aminopeptidase N) on macrophages/monocytes. To examine its immunomodulatory effect after high-dose therapy and autologous bone marrow transplantation (BMT), a dose-finding phase Ib trial was conducted with 30 Hodgkin's disease and non-Hodgkin's lymphoma patients who received no drug (control), 10 and 30 mg (low dose), or 90 and 180 mg (high dose) of bestatin daily for 60 days following autologous BMT. Bestatin administration was initiated when the absolute neutrophil count was greater than 250/mm3 on 2 consecutive days. The serum neopterin levels, an indicator of monocyte/macrophage activation, increased in the high-dose group compared to the control group (not significantly) and the low-dose group (significantly). Similarly, the colony-stimulating activity in the sera was significantly increased in the high-dose group compared to the control and low-dose groups. We also examined the expression of cell-surface markers on monocytes in these patients by fluorescent cytometry analysis. There was no significant difference either in the frequency or absolute number of monocytes (CD14+) among the three groups at any time. However, a significant increase in the frequency of CD16(FcgRIII)-positive monocytes (a marker of activation) was observed in the high-dose group compared to controls from day 14 to day 60 after the start of bestatin administration. Further, the frequency of HLA-DR+ monocytes (another marker of activation) was significantly increased in the high-dose group. These results indicate that bestatin at higher doses (90 and 180 mg daily), but not lower doses, activates macrophages/monocytes, as demonstrated by phenotypic marker (HLA-DR and CD16) up-regulation, and this provides augmentation of neopterin and colony-stimulating activity in the serum of patients following autologous BMT.
Ino
K
K
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha 68198-5660, USA.
Bierman
P J
PJ
Varney
M L
ML
Heimann
D G
DG
Kuszynski
C A
CA
Walker
S A
SA
Talmadge
J E
JE
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001708:Biopterins / Q000031:analogs & derivatives / Q000097:blood; D016026:Bone Marrow Transplantation; D003115:Colony-Stimulating Factors / Q000097:blood; D003131:Combined Modality Therapy; D005260:Female; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D019798:Neopterin; D017452:Receptors, IgG / Q000378:metabolism
D000276:Adjuvants, Immunologic; D003115:Colony-Stimulating Factors; D006684:HLA-DR Antigens; D017452:Receptors, IgG; D001708:Biopterins; D019798:Neopterin; D007930:Leucine; C012211:ubenimex