Serum levels of angiogenin, basic fibroblast growth factor and endostatin in patients receiving intensive chemotherapy for acute myelogenous leukemia

Abstract

Angiogenesis seems to be important both in the pathogenesis of acute myelogenous leukemia (AML) and for the susceptibility of AML blasts to chemotherapy. Recent clinical studies even suggest that antiangiogenic therapy can induce disease control in patients with AML relapse. In this context we have investigated the profile of the systemic component of angiogenic regulation in AML by characterizing the serum levels of (i) the angiogenic regulators angiogenin, basic fibroblast growth factor (bFGF) and endostatin; (ii) the endothelial cell marker soluble (s) E-selectin. Patients with untreated AML had increased levels of angiogenin, endostatin and sEselectin, whereas the levels of bFGF were not significantly altered. The systemic levels of the proangiogenic bFGF, the antiangiogenic endostatin and the endothelial cell marker sE-selectin showed significant correlations, whereas angiogenin and sE-selectin levels were not correlated. Furthermore, intensive chemotherapy resulted in decreased systemic levels of the 2 proangiogenic mediators angiogenin and bFGF, whereas endostatin levels remained high after treatment. Although angiogenin normally is a part of the acute phase reaction, its systemic levels were not altered when patients with chemotherapy-induced cytopenia developed complicating bacterial infections. Our results suggest that intensive chemotherapy can modulate the systemic component of angiogenic regulation in AML patients.

The possible role of matrix metalloproteinase (MMP)-2 and MMP-9 in cancer, e.g. acute leukemia

“…Under physiological conditions, it is known to circulate at low levels, whereas levels are increased during cancer progression. The reason for this rise in endostatin levels is not clear yet, but increased MMP-activity might play a role [49][50][51][52][53][54][55][56]. Endostatin was described to be able to inhibit proMMP-2 activation and inhibit MMP-2 activity in vitro.…”

The clinical potential of antiangiogenic fragments of extracellular matrix proteins

“…It is unclear whether these elevated endostatin levels are due to direct intratumoral production or a coordinated 'host' response to proangiogenic stimuli, in particular VEGF produced by the cancer (Feldman et al, 2002;Glenjen et al, 2002;Iizasa et al, 2004). What such findings do suggest however is that if this endogenous endostatin is in an active form, further increasing serum endostatin levels to pharmacological levels may not have a significant additional antiangiogenic effect as it is possible that in clinically manifest tumours, once the angiogenic switch has been tripped, raising the levels of endogenous antiangiogenic agents further is not very effective in resetting this.…”

Elevated serum endostatin levels is associated with favorable outcome in acute myeloid leukemia

“…Lai et al [7] did not fi nd signifi cant differences in the median plasma endostatin levels between AML/MDS patients and normal controls. On the other hand Gelenjen et al [11] and Wrobel et al [8] observed increased serum endostatin levels in untreated AML. Furthermore endostatin remains high even after induction chemotherapy.…”

“…In chronic lymphocytic leukemia and NHL no difference was found between endostatin plasma levels in complete remission and progressive disease. Morevoer endostatin serum levels did not correlate with disease free survival [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16].…”

“…The more elevation of endostatin levels at AML remission might represent a rebound effect after reduction of the tumor mass and subsequently reduction in the production of the secretion of proangiogenic factors while the production of inhibitors continue. The theory proposed that direct release of endostatin by the malignant cells is less likely due to (i) the lack of correlation between serum levels and release by in vitro cultured AML blasts; and (ii) the persistently increased levels even after massive reduction of the AML cell burden by induction therapy [11]. Wrobel et al [8] suggested that chemotherapy can modulate the systemic components of angiogenic regulation.…”