Modulation of myelopoiesis by CSF or CSF-inducing biological response modifiers.
We have compared the effects on number and function of bone marrow progenitors and peripheral effector cells of the myelomonocytic lineage of treatment with the 2-cyanaziridine compounds Azimexone and BM 41.332 to those of maleic anhydride divinyl ether copolymer (MVE-2) or granulocyte-macrophage colony stimulation factor (GM-CSF). Within a few hours after i.p. injection of either Azimexone or BM 41.332, there was a dose-dependent increase in serum CSF levels, CSF secretion by mononuclear bone marrow cells (BMC) and macrophages (M phi), which was followed by an increase in granulocyte-M phi committed stem cells (GM-CFU-C), nucleated BMC, and peripheral blood leukocytes. Optimal effects occurred 3 days after 50 mg/kg Azimexone or 25 mg/kg BM 41.332. Three i.p. injections of 50 mg/kg Azimexone into mice pretreated with cyclophosphamide (CY) (150 mg/kg) were able to significantly restore suppressed bone marrow cellularity (GM-CFU-C and nucleated BMC). Azimexone also increased the number of peripheral M phi in normal or CY-treated mice, without inducing detectable tumoricidal activity. These M phi, however, retained their capacity to become fully activated (cytotoxic) by appropriate activation signals such as IFN or LPS. Analogous to the 2-cyanaziridines. MVE-2 (at 25 mg/kg) had similar stimulatory effects on myeloid functions in normal mice. MVE-2 induced, in addition, a significant augmentation of cytoxicity by both M phi and NK cells. In contrast, single or multiple injections of semipurified GM-CSF into normal mice (1000 U or 5000 U per mouse) failed to detectably stimulate myelopoietic growth and differentiation. 2-cyanaziridine compounds thus offer the potential of selectively augmenting growth and differentiation of myelomonocytic cells in normal and bone marrow-depressed mice without appreciably affecting their immunological status.
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D001388:Aziridines / Q000494:pharmacology*; D001389:Azirines / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects; D003115:Colony-Stimulating Factors / Q000378:metabolism / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic; D066298:In Vitro Techniques; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011458:Prostaglandins E / Q000494:pharmacology; D011713:Pyran Copolymer / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects*
D000276:Adjuvants, Immunologic; D001388:Aziridines; D001389:Azirines; D003115:Colony-Stimulating Factors; D011458:Prostaglandins E; D011713:Pyran Copolymer; C035520:ciamexon; C016866:azimexon; D003520:Cyclophosphamide