lactoferrin and Myelodysplastic-Syndromes

Myelotoxicity remains a significant dose-limiting side effect of chemotherapy contributing to the morbidity and mortality of patients undergoing treatment for cancer. A number of different experimental approaches are being studied, both in the clinic and in the laboratory, in an attempt to prevent this iatrogenic complication. The present review provides a synopsis of the various myeloprotective strategies now being employed in experimental trials. Emphasis is placed on the use of putative physiologic bioregulatory molecules (lactoferrin, prostaglandin E, interferon) to prevent or lessen chemotherapy-induced myelotoxicity, with consideration also given to other promising treatment modalities (i.e., adenosine, lithium, diethyldithiocarbanate).

Topics: Adenosine; Antineoplastic Agents; Bone Marrow; Ditiocarb; Humans; Interferons; Lactoferrin; Leukocyte Count; Lithium; Myelodysplastic Syndromes; Prostaglandins E

Previous studies on neutrophils in patients with the myelodysplastic syndromes (MDS) have indicated deficiencies in the contents of primary and secondary granules. However, the granule membrane remains virtually unstudied despite its essential role in the dynamic function of the cytoplasmic granules. In this study, we examined the membrane glycoproteins of primary and secondary granules of peripheral blood and/or bone marrow neutrophils using the monoclonal antibody H36/71 to CD15 glycoproteins. In addition, myeloperoxidase activity and antigen, elastase and lactoferrin were also studied using cytochemical and immunocytochemical stains. A total of 216 patients were included. Deficiencies of granule membrane glycoproteins were the most common, detected in 49%, followed by myeloperoxidase activity (17%), elastase (16%), myeloperoxidase antigen (9%), and lactoferrin (8%). Multiple deficiencies always included granule membrane deficiency. We conclude that granule membrane defects are common in MDS, may provide a common mechanism for multiple granule deficiencies, and may prove to be an additional abnormality associated with granulocyte dysfunction.

Topics: Cytoplasmic Granules; Humans; Immunologic Deficiency Syndromes; Intracellular Membranes; Lactoferrin; Leukocyte Elastase; Lewis X Antigen; Membrane Glycoproteins; Myelodysplastic Syndromes; Neutrophils; Peroxidase

Myelodysplastic syndromes (MDS) are stem cell disorders of clonal origin in which infections and leukemic transformation are quite frequent. Neutrophils from 28 patients with MDS were analysed by flow cytometry for the expression of the two complement receptors CR1 and CR3, the antigenic reactivity of some granule constituents--myeloperoxidase, lysozyme, elastase, lactoferrin--and functional activities, such as locomotion, respiratory burst and cytotoxicity. The results were correlated with the FAB disease subtypes, grouped as low risk (RA) and high risk patients (RAEB, RAEB-t, CMML) and with 30 healthy subjects. A significant reduction in the percentage of neutrophil CR1, CR3 positivity and chemotaxis induced by endotoxin-activated serum was detected in the high risk group when compared with the low risk group and healthy controls. Furthermore, the high risk group also showed a low amount of myeloperoxidase, elastase, lysozyme and superoxide anion, but both low and high risk groups displayed reduced cellular cytotoxicity in comparison with the control. This work indicates that MDS patients belonging to the more advanced FAB categories frequently show multiple abnormalities in the expression of neutrophil complement receptors, and granular components (> 3), as well as in cell functions, suggesting the possibility of using these phenotypic abnormalities in the monitoring of disease progression.

Topics: Chemotaxis, Leukocyte; Cytoplasmic Granules; Flow Cytometry; Humans; Lactoferrin; Muramidase; Myelodysplastic Syndromes; Neutrophils; Pancreatic Elastase; Peroxidase; Phagocytosis; Receptors, Complement; Receptors, Complement 3b; Superoxides

Plasma lactoferrin content was measured before and after therapy with recombinant granulocyte-macrophage colony-stimulating factor in five patients with aplastic anaemia, six with myelodysplasia, and three with prolonged, severe, chemotherapy-induced neutropenia. Before therapy plasma lactoferrin content was uniformly low. However, patients with aplastic anemia and those with chemotherapy-induced neutropenia had a normal lactoferrin:neutrophil ratio. The low levels of plasma lactoferrin thus reflected the low granulocyte mass. On the other hand, patients with myelodysplasia also had reduced lactoferrin:neutrophil ratios, suggesting qualitative/quantitative abnormalities of neutrophil lactoferrin production. After treatment with granulocyte-macrophage colony-stimulating factor, plasma lactoferrin levels increased in patients with aplastic anemia and in those with chemotherapy-induced neutropenia who showed a neutrophil response to treatment. In these patients, the lactoferrin:neutrophil ratio became elevated, suggesting increased synthesis/release of lactoferrin from neutrophils. However, patients with myelodysplasia continued to show depressed lactoferrin:neutrophil ratios, even when there had been an increase in granulocyte count, suggesting persistent abnormalities of neutrophil lactoferrin production/release. The implications of these findings for treatment of neutropenic patients with granulocyte-macrophage colony-stimulating factors are discussed.

Topics: Adult; Anemia, Aplastic; Antineoplastic Agents; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Lactoferrin; Leukocyte Count; Male; Middle Aged; Myelodysplastic Syndromes; Neutropenia; Recombinant Proteins

Intracellular contents and serum levels of neutrophilic granule protein components, including myeloperoxidase (MPO), lactoferrin (LF) and lysozyme (LYZ), were investigated in 30 cases of myelodysplastic syndromes (MDS), with 59 healthy adult donors as controls. Both neutrophilic MPO and LF decreased significantly, suggesting the transformation of abnormal clones. Both serum levels of LF and LYZ exhibited a considerable fluctuation which may reflect reflect granulopoiesis in the bone marrow. We are of the opinion that measurement of intracellular MPO, LF, LYZ and their serum levels may aid in the diagnosis and prognosis of MDS and is proved to be of great clinical significance.

Topics: Adolescent; Adult; Child; Female; Humans; Lactoferrin; Male; Middle Aged; Muramidase; Myelodysplastic Syndromes; Neutrophils; Peroxidase

Neutrophils and band forms from patients with acute myeloid leukemia and myelodysplastic syndrome were stained for the presence of myeloperoxidase using a cytochemical method (diaminobenzidine/hydrogen peroxide) and the alkaline phosphatase--anti-alkaline phosphatase immunocytochemical procedure (using monoclonal anti-myeloperoxidase). Neutrophils and bands were also stained for elastase and lactoferrin using monoclonal and polyclonal antibodies, respectively. Subpopulations of neutrophils and bands from cases of acute myeloid leukemia and myelodysplasia exhibited a qualitative and/or quantitative deficiency in myeloperoxidase. In addition, a quantitative decrease in elastase and/or lactoferrin staining was detected. Thus, neutrophils and bands from patients with acute myeloid leukemia and myelodysplastic syndrome have a defect in one or more of the constituents of primary and/or secondary granules. These defects are consistent with the view that abnormal neutrophils and bands are derived from a malignant clone of myeloid precursor cells.

Topics: Cytoplasmic Granules; Humans; Immunohistochemistry; Lactoferrin; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Neutrophils; Pancreatic Elastase; Peroxidase