angiogenin and Leukemia--Myeloid

Thalidomide is a putative anti-angiogenesis agent that has significant anti-tumour activity in haematological malignancies with increased bone marrow angiogenesis, including multiple myeloma (MM) and myelodysplastic syndromes (MDS). Increased levels of the mitogen for angiogenesis, vascular endothelial growth factor (VEGF), correlate with worse survival in acute myeloid leukaemia (AML). A phase II trial of thalidomide was conducted in patients with relapsed- or refractory-AML previously treated with cytarabine-containing regimens. A total of 16 patients with refractory- or relapsed-AML were treated with thalidomide 200-800 mg orally daily (median dose 400 mg daily) for a median of 27 d (range, 3-94 d). Overall, one patient (6%) achieved complete remission (CR) lasting for 36 months, and two patients had a transient reduction in marrow blasts from 8% and 7% to less than 5% in both cases. There was no correlation between reduction in levels of angiogenesis markers and response. Toxicities related to thalidomide were significant, and precluded dose escalation beyond 400 mg orally daily in most patients. Although there appears to be some evidence of biological activity, single agent thalidomide is not an optimal choice of therapy for salvaging patients with relapsed- or refractory-AML. Thalidomide analogues with more potent immunomodulatory activities and more favourable toxicity profiles may offer more promise as anti-AML therapy.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Biomarkers; Fibroblast Growth Factor 2; Hepatocyte Growth Factor; Humans; Leukemia, Myeloid; Middle Aged; Recurrence; Ribonuclease, Pancreatic; Thalidomide; Treatment Outcome; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Angiogenesis is of prognostic importance not only in solid tumors but also in malignant blood diseases. We measured levels of vascular endothelial growth factor (VEGF), angiogenin (ANG), and basic fibroblast growth factor (bFGF) in peripheral blood samples from 65 patients with myelodysplastic syndrome (MDS), from 25 patients with de novo acute myeloid leukemia (AML), and from 50 healthy donors. In matched samples, VEGF levels in serum were substantially higher than VEGF levels in plasma (380.7 +/- 56 pg/ml vs. 45.3 +/- 4.5 pg/ml, mean +/- SEM, p < 0.001), whereas serum and plasma levels of ANG were comparable and significantly correlated (r = 0.8; p < 0.01). Compared to normal controls (1.3 +/- 0.09 pg), serum levels of VEGF corrected for the peripheral blood platelet count (VEGF/10(6) platelets, VEGF(PLT)) were elevated in patients with refractory anemia (RA; 3.1 +/- 0.8 pg, p < 0.01), and reached maximal values in patients with advanced stage MDS (RAEB, RAEB-t) (3.5 +/- 0.6 pg, p < 0.001), de novo AML (3.6 +/- 1.1 pg, p < 0.05), and chronic myelomonocytic leukemia (CMML; 3.7 +/- 0.9 pg; p < 0.001). Levels of soluble ANG were elevated in RA (351 +/- 25.7 ng/ml, p < 0.001), in RAEB/RAEB-t (402 +/- 17.9 ng/ml; p < 0.001), in CMML (413.8 +/- 29.5 ng/ml; p < 0.001), and in patients with AML (305.1 +/- 17.1 ng/ml; p < 0.01, controls 255.4 +/- 8.1 ng/ml). Serum bFGF was neither elevated in MDS nor in AML patients. These results suggest that VEGF(PLT) is a marker of disease progression in MDS. Moreover, we show for the first time that elevated blood levels of ANG can be found in patients with myeloid malignancies, suggesting a role of ANG in the pathogenesis of these diseases.

Topics: Acute Disease; Case-Control Studies; Disease Progression; Endothelial Growth Factors; Female; Fibroblast Growth Factor 2; Humans; Intercellular Signaling Peptides and Proteins; Leukemia, Myeloid; Lymphokines; Male; Middle Aged; Myelodysplastic Syndromes; Neoplasm Proteins; Ribonuclease, Pancreatic; Solubility; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Nitric oxide (NO) inhibits growth and induces differentiation in acute myeloid leukaemia (AML) cells. To identify genes associated with these processes, we studied the effect of NO on AML gene expression using the technique of Representational Difference Analysis. Exposure of HL-60 cells to the NO donor DETA-NO for 24 h induced the expression of a novel gene that was named rno (regulated by nitric oxide). Treatment of HL-60 cells with dimethyl sulphoxide induced expression of rno, but treatment with Vitamin D3 or all-trans retinoic acid did not. Upregulation of rno by NO was cGMP independent. Northern blot analysis indicated that constitutive expression of the novel gene was limited to leucocytes. Three isoforms of rno were identified. An rno cDNA clone was obtained by screening a human leucocyte library. The nucleotide sequence of the open reading frame shared significant homology with that of the human ribonuclease/angiogenin inhibitor (RI). The predicted amino acid sequence indicated that, like RI, rno is leucine and cysteine rich and is comprised of a series of repetitive elements (leucine-rich repeats) that may mediate macromolecular interactions. Enhancement of expression of rno may be a component of the process by which differentiation and growth inhibition of leukaemia cells is induced by NO.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Acute Disease; Amino Acid Sequence; Base Sequence; Blotting, Northern; Enzyme Inhibitors; Gene Expression Regulation; Guanylate Cyclase; HL-60 Cells; Humans; Leukemia, Myeloid; Leukocytes; Molecular Sequence Data; Nitric Oxide Donors; Protein Isoforms; Proteins; Repetitive Sequences, Amino Acid; Reverse Transcriptase Polymerase Chain Reaction; Ribonuclease, Pancreatic; Sequence Homology, Nucleic Acid; Sulfuric Acid Esters; Triazenes

Human angiogenin is a potent inducer of angiogenesis. The association between angiogenin and cancer progression and poor outcome in solid tumours has been documented, but its significance in leukaemias has not been evaluated. We evaluated plasma angiogenin levels in 101 previously untreated patients with acute myeloid leukaemia (AML) (59 patients) and advanced myelodysplastic syndrome (MDS) (42 patients). Angiogenin levels were significantly higher in AML and advanced MDS patients than in healthy individuals (P < 0.00001). Angiogenin levels were also significantly higher in advanced MDS than in AML (P = 0.001). Higher levels of angiogenin correlated with prolonged survival periods in both AML and advanced MDS patients (P = 0.02 and 0.01 respectively). We found no correlation between angiogenin plasma level and various patient characteristics, including age, performance status, antecedent haematological disorder, haemoglobin, white blood cell and platelet counts, and poor prognosis cytogenetics. There was no significant correlation between angiogenin level and complete remission rate and duration in AML or advanced MDS patients. In multivariate analysis, angiogenin concentration retained its significance as a prognostic factor in AML (P = 0.03), together with age (P = 0.00007) and haemoglobin (P = 0.03).

Topics: Acute Disease; Biomarkers; Case-Control Studies; Disease Progression; Enzyme-Linked Immunosorbent Assay; Follow-Up Studies; Humans; Leukemia, Myeloid; Middle Aged; Multivariate Analysis; Myelodysplastic Syndromes; Ribonuclease, Pancreatic; Survival Rate