transforming-growth-factor-beta and Anemia--Refractory

The myelodysplastic syndromes are a heterogeneous group of clonal diseases of haemopoiesis, which are a challenge for both biologists and clinicians. In this paper the current classification and the recent advances in the understanding the disease mechanisms are reviewed. The recent therapeutic advances are also indicated, such as intensive and low-dose chemotherapy, new drugs, erythropoietin and colony-stimulating factors. However, the work has been focused on thalidomide, its therapeutic potential, its modes of actions, side effects, indications and future applications.

Topics: Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Antineoplastic Agents; Chromosome Aberrations; Constipation; Cytokines; Dyspnea; Fatigue; Humans; Immunosuppressive Agents; Interleukin-1; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes; Thalidomide; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) are cytokines that play key roles in the myelodysplastic syndrome (MDS). There have been several reports on the presence of genetic polymorphisms in the DNA sequence encoding the leader sequence of the TGF-beta1 protein, located in codon 10 in exon 1 and in the -308 promoter region of TNF-alpha. The objective of this study was to investigate the association between TNF-alpha and TGF-beta1 gene polymorphisms and the susceptibility to MDS and the progression of the disease among patients with MDS belonging to the refractory anemia (RA) subtype.. The diagnosis of MDS (n = 50) was based on the FAB criteria. The TNF-alpha genotypes were analyzed by PCR-RFLP and the TGF-beta genotypes were analyzed using an amplification refractory mutation system.. Compared with healthy control subjects, patients with RA showed no significant deviations in genotype or allele frequencies of TNF-alpha. The TT homozygosity at codon 10 of TGF-beta1 was significantly higher among patients with bi- or pancytopenia (severe group) than in the patients with anemia only (mild group; odds ratio = 6.99, p = 0.003). These findings suggest that the TGF-beta1 gene polymorphism in codon 10 and the -308 TNF-alpha gene polymorphism do not predispose to the development of RA, but the TGF-beta1 gene polymorphism may affect disease progression.

Topics: Adult; Aged; Aged, 80 and over; Alleles; Anemia, Refractory; DNA; DNA Mutational Analysis; Female; Gene Frequency; Genotype; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Promoter Regions, Genetic; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

We examined the involvement of apoptosis with myelodysplastic syndrome (MDS) accompanied by peripheral cytopenias despite normo-hypercellular bone marrow.. Bone marrow smears from 31 patients with MDS-refractory anemia (RA) and five normal controls were stained using the in situ end labeling (ISEL) method. Next, the inhibitory effects of a caspase-3 inhibitor, matrix metalloproteinase inhibitor (MMPI), anti-tumor necrosis factor (TNF)-alpha or anti-Fas antibody upon the apoptosis induction in overnight cultures of bone marrow cells from the patients were examined. Further, TNF-alpha, transforming growth factor (TGF)-beta and soluble Fas ligand (sFasL) concentrations in culture supernatants of the cells were assessed by enzyme-linked immunosorbent assay (ELISA).. The incidence of ISEL-positive cells among MDS patients was significantly higher than in normal controls (50.8 +/- 14.0% vs. 11.3 +/- 2.4%; P < 0.0001). A caspase-3 inhibitor reduced significantly the ISEL-positive rates (32.6 +/- 15.2% vs. 50.2 +/- 16.5%; P < 0.0001). Anti-TNF-alpha or anti-Fas antibody reduced the ISEL-positive rates significantly (28.2 +/- 6.0%, 29.2 +/- 5.8%, vs. 44.2 +/- 3.4%, P < 0.001, P = 0.001, respectively). KB-R7785 also significantly decreased the ISEL-positive rates (18.0 +/- 9.3% vs. 43.6 +/- 14.0%; P < 0.0001). The concentration of TNF-alpha was significantly reduced by KB-R7785 (P < 0.05), whereas that of TGF-beta was not. Concentration of sFasL was under detectable level in the present assay system. The derivatives of KB-R7785 that can be administrated orally showed inhibitory effect on apoptosis induction as well.. These findings suggest that MMPIs inhibits the apoptosis induction of MDS bone marrow cells via the inhibition of TNF-alpha and probably sFasL secretion, and that MMPIs can be used to control the abnormal induction of apoptosis in MDS.

Topics: Adult; Aged; Anemia, Refractory; Antibodies; Apoptosis; Bone Marrow Cells; Caspase 3; Caspase Inhibitors; Cytokines; Enzyme Inhibitors; Fas Ligand Protein; fas Receptor; Humans; Matrix Metalloproteinase Inhibitors; Membrane Glycoproteins; Middle Aged; Protease Inhibitors; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Labeling index (LI), apoptosis, levels of 2 pro-apoptotic cytokines tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta(TGF-beta), and the number of monocyte/macrophage cells that are the likely source of the cytokines were simultaneously measured in plastic-embedded bone marrow (BM) biopsy sections of 145 patients with myelodysplastic syndromes (MDS). TNF-alpha was correlated with TGF-beta (P = .001) and with monocyte/macrophage cells (P = .003). Patients with excess blasts in their marrows had a higher TGF-beta level (P = .01) and monocyte/macrophage number (P = .05). In a linear regression model,TGF-beta emerged as the most significant biological difference between patients who have excess of blasts and those who do not (P = .01). We conclude that in addition to TNF-alpha, TGF-beta also plays a significant role in the initiation and pathogenesis of MDS, and that a more precise definition of its role will likely identify better preventive and therapeutic strategies.

Topics: Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Animals; Apoptosis; Bone Marrow Cells; Cell Division; Cytokines; Female; Humans; Leukemia, Myelomonocytic, Chronic; Macrophages; Male; Monocytes; Myelodysplastic Syndromes; Regression Analysis; S Phase; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha