epiglucan and Lymphoma

This study was conducted as a prospective, multicenter trial to evaluate the efficacy and safety of micafungin as an empirical therapy for suspected invasive fungal infections (IFIs), including febrile neutropenia (FN), and to evaluate the usefulness of β-D: -glucan (BG) and Aspergillus galactomannan (GM) antigen in patients with hematologic diseases. A total of 121 patients were enrolled and assessed for safety, and 119 were examined for clinical efficacy. The main underlying diseases were acute myeloid leukemia (38.0%), acute lymphoblastic leukemia (18.2%), and malignant lymphoma (18.2%). The median initial daily dose and duration of micafungin treatment were 150 mg/day and 13 days, respectively. The overall response rate for suspected IFIs (n = 119), based on four composite endpoints, including baseline IFI, breakthrough IFIs (proven and probable), survival, and premature discontinuation, was 79.0%. In addition, the response rate for FN (n = 81), based on these four endpoints as well as defervescence during neutropenia, was 39.5%. Breakthrough IFIs (proven, probable, and possible) occurred in five patients during micafungin treatment. All of these patients were positive for either BG or GM before the breakthrough IFIs. The incidence of adverse events (AEs) associated with micafungin was 10.7% and most were mild. The majority of AEs were liver dysfunction. These results indicate the effectiveness and safety of micafungin as an empirical therapy for suspected IFIs, including FN, and the usefulness of monitoring both BG and GM to detect breakthrough IFIs.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antifungal Agents; Antigens, Bacterial; Aspergillosis; beta-Glucans; Candidiasis, Invasive; Chemical and Drug Induced Liver Injury; Early Diagnosis; Echinocandins; Female; Galactose; Hematologic Neoplasms; Humans; Leukemia, Myeloid, Acute; Lipopeptides; Lymphoma; Male; Mannans; Micafungin; Middle Aged; Mycoses; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Young Adult

Beta-(1,3)/(1,6) D-glucan, a component of the fungal cell wall, has been shown to stimulate the immune system, enhance hematopoiesis, amplify killing of opsonized tumor cells and increase neutrophil chemotaxis and adhesion. In view of these attributes, the beta-glucans should be studied for both their therapeutic efficacy in patients with cancer as well as an adjunctive therapy in patients receiving chemotherapy as a maneuver to limit suppression of hematopoiesis.In this study, twenty patients with advanced malignancies receiving chemotherapy were given a beta-(1,3)/(1,6) D-glucan preparation (MacroForce plus IP6, ImmuDyne, Inc.) and monitored for tolerability and effect on hematopoiesis. Our results lead us to conclude that beta-glucan is well-tolerated in cancer patients receiving chemotherapy, may have a beneficial effect on hematopoiesis in these patients and should be studied further, especially in patients with chronic lymphocytic leukemia and lymphoma.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; beta-Glucans; Female; Hematopoiesis; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma; Male; Middle Aged; Neoplasms; Proteoglycans

β-glucans are polysaccharides that activate innate immunity. We herein investigated whether P-glucans promote the immunological effects of antibody drugs against malignant tumor cells using human peripheral blood mononuclear cells (PBMCs). Rituximab bound to CD20-specific lymphoma and exhibited cytotoxic activity in the presence of human mononuclear cells, but not neutrophils. The addition of Sparassis crispa (cauliflower mushroom)-derived β-glucan (SCG) and granulocyte macrophage colony-stimulating factor (GM-CSF) to co-cultures of PBMCs and Raji lymphoma cells further promoted antibody-dependent cell-mediated cytotoxicity (ADCC). The GM-CSF treatment increased β-glucan receptor expression on adherent cells in PBMCs. A co-stimulation with GM-CSF and SCG of PBMCs induced an increase in the number of spreading cells and the activation of natural killer (NK) cells. The enhancement in ADCC was abolished by the removal of NK cells, indicating that SCG and GM-CSF increased ADCC against lymphoma by activating β-glucan receptor-expressing cells in PBMCs and enhancing NK cell activity. The synergistic mechanisms of action of mushroom-derived β-glucans and biopharmaceuticals, including recombinant cytokines and antibodies, in the treatment of malignant tumor cells provide important insights into the clinical efficacy of β-glucans from mushrooms.

Topics: Agaricales; beta-Glucans; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Killer Cells, Natural; Leukocytes, Mononuclear; Lymphoma; Lymphoma, B-Cell

Beta-(1-3),(1-6)-D-glucans demonstrate antitumor effects in vivo due to the activation of innate immune cells. Cyclophosphamide (CY) enhances natural or therapeutically induced antitumor immune responses by reducing the number and activity of regulatory T (Treg) cells.. We tested whether oral administration of soluble beta-glucan augmented the inhibitory effect of intraperitoneally injected low-dose CY (30 mg/kg) on subcutaneously growing A20-lymphoma in Balb/c-mice.. Administration of CY one week after tumor inoculation significantly diminished tumor growth (p=0.009) and the absolute number of Treg cells in the peripheral blood compared with phosphate buffered saline-treated mice (p=0.036). Treatment of CY pre-conditioned lymphoma-bearing mice with daily beta-glucan (400 μg/mouse) between day 9 and day 13 after tumor injection significantly delayed onset of tumor growth, compared to mice which received only CY (p=0.01).. Beta-(1-3),(1-6)-D-glucan could be useful in the treatment of lymphoma after low-dose chemotherapy with CY.

Topics: Animals; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Drug Synergism; Female; Glucans; Injections, Intraperitoneal; Lymphoma; Mice; Mice, Inbred BALB C; Mice, Nude; T-Lymphocytes, Regulatory; Tumor Cells, Cultured

Anti-tumor mAbs hold promise for cancer therapy, but are relatively inefficient. Therefore, there is a need for agents that might amplify the effectiveness of these mAbs. One such agent is beta-glucan, a polysaccharide produced by fungi, yeast, and grains, but not mammalian cells. Beta-glucans are bound by C receptor 3 (CR3) and, in concert with target-associated complement fragment iC3b, elicit phagocytosis and killing of yeast. Beta-glucans may also promote killing of iC3b-opsonized tumor cells engendered by administration of anti-tumor mAbs. In this study, we report that tumor-bearing mice treated with a combination of beta-glucan and an anti-tumor mAb show almost complete cessation of tumor growth. This activity evidently derives from a 25-kDa fragment of beta-glucan released by macrophage processing of the parent polysaccharide. This fragment, but not parent beta-glucan, binds to neutrophil CR3, induces CBRM 1/5 neoepitope expression, and elicits CR3-dependent cytotoxicity. These events require phosphorylation of the tyrosine kinase, Syk, and consequent PI3K activation because beta-glucan-mediated CR3-dependent cytotoxicity is greatly decreased by inhibition of these signaling molecules. Thus, beta-glucan enhances tumor killing through a cascade of events, including in vivo macrophage cleavage of the polysaccharide, dual CR3 ligation, and CR3-Syk-PI3K signaling. These results are important inasmuch as beta-glucan, an agent without evident toxicity, may be used to amplify tumor cell killing and may open new opportunities in the immunotherapy of cancer.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; beta-Glucans; Cell Line, Tumor; Complement C3b; Humans; Injections, Intravenous; Intracellular Signaling Peptides and Proteins; Lymphoma; Macrophage-1 Antigen; Macrophages; Mice; Mice, Inbred C57BL; Opsonin Proteins; Phosphatidylinositol 3-Kinases; Protein-Tyrosine Kinases; Signal Transduction; Survival Analysis; Syk Kinase; Yeasts

By activating complement, antitumor monoclonal antibodies coat tumor cells with iC3b. beta-glucans, naturally occurring glucose polymers, bind to the lectin domain of the leukocyte receptor CR3, prime it for binding to iC3b, and trigger cytotoxicity of iC3b-coated tumor cells. We studied the combination of the complement-activating antibody rituximab with barley-derived (1-->3),(1-->4)-beta-D-glucan (BG) against CD-20 positive lymphoma xenografts in SCID mice. Growth of established subcutaneous non-Hodgkin's lymphoma (NHL) (Daudi and EBV-derived B-NHL) or Hodgkin's disease (Hs445 and RPMI6666) was significantly suppressed in mice treated with a combination of intravenous rituximab and oral BG, when compared to mice treated with rituximab or BG alone. Survival of mice with disseminated lymphoma was significantly increased in the combination group as compared to other treatment groups. No clinical toxicity was observed. The therapeutic efficacy and lack of toxicity of this combination supports further investigation into its clinical utility.

Topics: Administration, Oral; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; beta-Glucans; Cell Line, Tumor; Drug Screening Assays, Antitumor; Drug Synergism; Female; Humans; Injections, Subcutaneous; Lymphoma; Mice; Mice, SCID; Neoplasm Transplantation; Rituximab; Survival Analysis; Time Factors; Transplantation, Heterologous; Xenograft Model Antitumor Assays

Intravenous and orally administered beta-glucans promote tumor regression and survival by priming granulocyte and macrophage C receptor 3 (CR3, iC3bR and CD11b/CD18) to trigger the cytotoxicity of tumor cells opsonized with iC3b via anti-tumor Abs. Despite evidence for priming of macrophage CR3 by oral beta-glucan in vivo, the current study in C57BL/6 and BALB/c mice showed that granulocytes were the essential killer cells in mAb- and oral beta-glucan-mediated tumor regression, because responses were absent in granulocyte-depleted mice. Among granulocytes, neutrophils were the major effector cells, because tumor regression did not occur when C5a-dependent chemotaxis was blocked with a C5aR antagonist, whereas tumor regression was normal in C3aR(-/-) mice. Neutrophil recruitment by C5a in vivo required amplification via leukotriene B(4), because both C5a-mediated leukocyte recruitment into the peritoneal cavity and tumor regression were suppressed in leukotriene B(4)R-deficient (BLT-1(-/-)) mice.

Topics: Administration, Oral; Animals; Antibodies, Monoclonal; beta-Glucans; Cell Line, Tumor; Chemotaxis, Leukocyte; Complement C3a; Complement C5a; Granulocytes; Killer Cells, Natural; Leukotriene B4; Lymphoma; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration; Receptors, Leukotriene B4

Efficacy of fluconazole (FLCZ), an anti-fungal agent of triazole derivatives, was evaluated in patients with systemic mycoses and suspected mycoses associated with hematologic malignancies including leukemia, myelodysplastic syndrome and malignant lymphoma. Plasma beta-D-glycan levels, the differences between the levels determined toxicolor test and in endospecy test, were also investigated. Fourteen patients with systemic mycoses and 31 patients with suspected mycotic infections were treated with intravenous administration of FLCZ at a daily dose of 400 mg. Excellent to good responses were observed in 4 of the 14 patients (28.6%) with definitive diagnosis of mycosis, and in 18 of the 31 patients (58.1%) with suspected fungal infections, with an overall efficacy rate of 48.9% (22/45). Levels of plasma beta-D-glycan correlated well with efficacies of FLCZ in 19 of 30 patients. In several cases, however, plasma beta-D-glucan levels were low during the entire course of treatment. Even in 10 cases of definite mycosis, 4 cases showed low levels of plasma beta-D-glucan (below 15 pg/ml by repeated determinations). The results indicate that FLCZ is an effective agent for the treatment of severe systemic fungal infections in patients with hematologic disorders. Deep seated mycosis cannot be ruled out even when its plasma levels of beta-D-glucan are low.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; beta-Glucans; Biomarkers; Drug Evaluation; Female; Fluconazole; Glucans; Humans; Leukemia; Lymphoma; Male; Middle Aged; Mycoses

It has been reported that beta-1,3-D-glucan isolated from Alcaligenes faecalis (TAK) promoted tumor cytolysis by mouse polymorphonuclear leukocytes (PMN). We investigated the effect of serum on mouse PMN tumor cytolysis induced by TAK and other PMN stimulators. Addition of fetal calf serum (FCS) to the cytolysis assay enhanced tumor cytolysis by PMN in a dose-dependent manner. Sera obtained from horses, mice, and rats were also effective enhancers of PMN tumor cytolysis. When FCS was added after the assay was under way, the enhancing effect decreased proportionally to the time elapsed. The enhancing activity was detected over a broad range of fractions with a peak at 170 kD by fractionation on a Superose 6 column. The responsible factor(s) in serum was stable after treatment at 60 degrees C, 30 min or after lowering the pH to 2. Mouse PMN stimulated with TAK increased production of hydrogen peroxide in the presence of FCS.

Topics: Alcaligenes; Animals; beta-Glucans; Blood; Cattle; Cytotoxicity, Immunologic; Glucans; Horses; Hydrogen Peroxide; Lymphokines; Lymphoma; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Neoplasms, Experimental; Neutrophils; Rats; Tumor Cells, Cultured