Hematopoietic and hematologic properties of bestatin in normal and cyclophosphamide myelosuppressed mice.
Bestatin is a potent inhibitor of aminopeptidase, an enzyme found in abundance in the membrane of monocytes and macrophages. Following binding of bestatin to cells in the histiocytic lineage, the production of colony stimulating activity is upregulated (both in vitro and in vivo) with subsequent increases in hematopoietic and hematologic parameters. We report that the frequency and absolute numbers of CFU-GM as well as entry of CFU-GM into S phase (a measure of progenitor cell activity) is upregulated by treatment of animals with bestatin. This results in an increase in bone marrow cellularity in cyclophosphamide suppressed mice and an increase in the absolute neutrophil count in normal and suppressed mice. The therapeutic application of this hematopoietic modulator has been demonstrated in combination cyclophosphamide and bestatin therapeutic protocols. Because this indication for bestatin has only recently been recognized, few clinical studies have been undertaken utilizing appropriate surrogates of hematopoietic activity. However, preliminary clinical evidence of hematopoietic activity by this non-toxic dipeptide, as reviewed here, suggests that this may be an appropriate strategy for the treatment of myelosuppressed patients.
Talmadge
J E
JE
SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.
Black
P L
PL
Pelus
L M
LM
Abe
F
F
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D001853:Bone Marrow / Q000276:immunology*; D002452:Cell Count / Q000187:drug effects; D003520:Cyclophosphamide / Q000494:pharmacology* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D007108:Immune Tolerance / Q000187:drug effects*; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000556:secondary; D051379:Mice
D003520:Cyclophosphamide; D000626:Aminopeptidases; D007930:Leucine; C012211:ubenimex