Hematopoietic and therapeutic properties of bestatin in normal and myelosuppressed mice.
Bestatin is a potent inhibitor of aminopeptidase B, an enzyme which is found in abundance in the membrane of monocytes and macrophages. Binding of Bestatin to cells in the histiocytic linage upregulates colony stimulating activity (both in vitro and in vivo), which subsequently increases hematopoietic and hematologic values. We report that the treatment of mice with Bestatin upregulates the frequency and absolute numbers of colony forming unit--granulocyte-macrophage (CFU-GM), as well as the entry of CFU-GM into S phase (a measure of progenitor cell activity). As a result, there is an increase in bone marrow cellularity in cyclophosphamide myelosuppressed mice and an increase in the absolute neutrophil count in normal and myelosuppressed mice. The therapeutic application of this hematopoietic modulator has been demonstrated in combination cyclophosphamide and Bestatin protocols. While Bestatin has significant therapeutic activity for minimal metastatic disease, therapy models in which the hosts have greater metastatic tumor burdens requires combination chemoimmunotherapy for a significant therapeutic effect. Because myelosuppression as a therapeutic indication for Bestatin has only recently been recognized, few clinical studies have been undertaken with appropriate surrogates of hematopoietic activity. However, the preliminary clinical evidence of hematopoietic activity by this non-toxic dipeptide, as reviewed here, suggests that this may be an appropriate drug for the treatment of myelosuppressed patients. Thus, Bestatin as an orally active biological response modifier (BRM) has significant therapeutic activity for metastatic disease via multiple mechanisms including hematopoietic stimulation and macrophage activating properties.
Talmadge
J E
JE
Immunotherapeutic Consultants, West Chester, PA 19355.
Pelus
L M
LM
Black
P L
PL
Abe
F
F
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001855:Bone Marrow Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology; D004359:Drug Therapy, Combination; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D007930:Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL
D000903:Antibiotics, Antineoplastic; D003520:Cyclophosphamide; D007930:Leucine; C012211:ubenimex