In vitro and in vivo hematopoietic activities of Betafectin PGG-glucan.
Betafectin PGG-glucan is a novel beta-(1,3)glucan that has broad-spectrum anti-infective activities without cytokine induction. Here we report that PGG-glucan also has both in vitro and in vivo hematopoietic activities. In vitro studies with bone marrow target cells from the C3H/HeN mouse revealed that although PGG-glucan alone had no direct effect on hematopoietic colony-forming cell (CFC) growth, when combined with granulocyte colony-stimulating factor (CSF) or granulocyte-macrophage CSF, it increased CFC numbers 1.5- to 2.0-fold over those obtained with CSFs alone. Bone marrow cells cultured for high-proliferative-potential CFCs in the presence of interleukin (IL)-1, IL-3, macrophage CSF, and stem cell factor (SCF), or cultured for erythroid burst-forming units in the presence of IL-3, SCF, and erythropoietin, also exhibited enhanced growth in the presence of PGG-glucan. The synergistic effect of PGG-glucan was specific and could be abrogated by anti-PGG-glucan antibody. The ability of PGG-glucan to modulate hematopoiesis in vivo was evaluated in myelosuppressed rodents and primates. C3H/HeN female mice were intravenously administered saline solution or PGG-glucan (0.5 mg/kg) 24 hours before the intraperitoneal administration of cyclophosphamide (200 mg/kg), and the recovery of bone marrow cellularity and granulocyte-macrophage progenitor cells was evaluated on days 4 and 8 after cyclophosphamide treatment. At both time points, enhanced hematopoietic recovery was observed in PGG-glucan-treated mice compared with saline-treated control mice. In a final series of in vivo experiments, we evaluated the ability of therapeutically administered PGG-glucan to enhance hematopoietic recovery in cyclophosphamide-treated cynomolgus monkeys. Monkeys received intravenous infusions of cyclophosphamide (55 mg/kg) on days 1 and 2, followed on days 3 and 10 by intravenous infusion of PGG-glucan (0.5, 1.0, or 2.0 mg/kg). Compared with those in saline-treated monkeys, accelerated white blood cell recovery and a reduction in the median duration of neutropenia were observed in PGG-glucan-treated monkeys. These studies illustrate that PGG-glucan has both in vitro and in vivo hematopoietic activities and that this agent may be useful in the prevention and/or treatment of chemotherapy-associated myelosuppression.
Patchen
M L
ML
Alpha-Beta Technology, Worcester, Massachusetts 01605, USA. mpatch@abti.com
Vaudrain
T
T
Correira
H
H
Martin
T
T
Reese
D
D
D000818:Animals; D000890:Anti-Infective Agents; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D003114:Colony-Forming Units Assay; D003520:Cyclophosphamide / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D005936:Glucans / Q000494:pharmacology*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006098:Granulocytes / Q000166:cytology; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D007958:Leukocyte Count; D008252:Macaca fascicularis; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009504:Neutrophils; D047071:beta-Glucans
D000890:Anti-Infective Agents; D005936:Glucans; D047071:beta-Glucans; C069894:poly-1-6-glucopyranosyl-1-3-glucopyranose glucan; D016179:Granulocyte Colony-Stimulating Factor; D003520:Cyclophosphamide