angiogenin and Multiple-Myeloma

There is limited data regarding the efficacy and safety of lenalidomide, adriamycin and dexamethasone (RAD) combination on newly diagnosed multiple myeloma (NDMM) patients. There is also scarce information about the effect of lenalidomide on bone metabolism and angiogenesis in NDMM. Thus, we conducted a Phase 2 study to evaluate the efficacy and safety of RAD regimen as induction in transplant-eligible NDMM patients and we studied the effects on bone metabolism and angiogenesis. A total of 45 patients were enrolled. Following four cycles of RAD, the overall response rate was 66.7% and after a median follow up of 29.1 months (range 21.0-34.9), the median survival outcomes have not been reached yet. RAD had a favorable toxicity profile and did not impair stem cell collection. RAD significantly reduced bone resorption markers CTX (p = 0.03) and TRACP-5b (p < 0.01). Interestingly, RAD also increased bone formation markers bone-specific alkaline phosphatase (p = 0.036), procollagen type 1 amino-terminal propeptide (p = 0.028) and osteocalcin (p = 0.026), which has not been described before with lenalidomide-containing regimens in the absence of bortezomib coadministration. Furthermore, the angiogenic cytokines VEGF (p = 0.01), angiogenin (p = 0.02) and bFGF (p < 0.01) were significantly reduced post-RAD induction. Our results suggest that RAD is an effective induction regimen before autologous stem cell transplantation with beneficial effects on bone metabolism and angiogenesis.

Topics: Adult; Aged; Alkaline Phosphatase; Angiogenic Proteins; Antineoplastic Combined Chemotherapy Protocols; Bone Resorption; Dexamethasone; Doxorubicin; Drug Therapy, Combination; Female; Fibroblast Growth Factor 2; Gene Expression Regulation, Neoplastic; Humans; Induction Chemotherapy; Lenalidomide; Male; Middle Aged; Multiple Myeloma; Osteocalcin; Peptide Fragments; Procollagen; Ribonuclease, Pancreatic; Treatment Outcome; Vascular Endothelial Growth Factor A

The aim of the study is to estimate whether bone marrow mast cell density (MCD) in multiple myeloma (MM) correlates with circulating levels of various angiogenic factors.. In 70 patients with newly diagnosed active MM, we measured MCD using immunohistochemical stain for tryptase and serum levels of matrix metalloproteinase 9 (MMP-9), angiopoietin 2 (ANGIOP-2), and angiogenin (ANG) with ELISA.. Levels of MCD, ANGIOP-2, and ANG were significantly higher in MM patients compared with the control group. The MMP-9 level was higher in MM patients compared with the control group but without statistical significance. All values were increasing in parallel with clinical stages. Furthermore, MCD correlated positively with MMP-9, ANGIOP-2, and ANG.. MCs participate in the angiogenic processes of MM, with complex implicated mechanisms. This interplay between MCs and the other participants favors angiogenesis and MM growth.

Topics: Aged; Aged, 80 and over; Cell Count; Cytokines; Female; Humans; Male; Mast Cells; Matrix Metalloproteinase 9; Middle Aged; Multiple Myeloma; Neovascularization, Pathologic; Ribonuclease, Pancreatic

In multiple myeloma (MM), angiogenesis plays a substantial role in disease progression. Interleukin-8 (IL-8), a pro-inflammatory chemokine with potent pro-angiogenic properties, has been implicated in the pathophysiology of MM. The aim of the study is to measure serum levels of IL-8 in MM patients and to correlate them with markers of angiogenesis, such as circulating levels of platelet derived growth factor-AB (PDGF-AB) and angiogenin (Ang), and bone marrow microvascular density (MVD). Fifty-three newly diagnosed MM patients, 23 of them, who reached plateau phase after effective treatment and 20 healthy controls, were studied. Serum levels of PDGF-AB, Ang and IL-8 were measured by ELISA, whereas bone marrow MVD was estimated by immunohistochemical staining of vessels with anti-CD31. All measured parameters were higher in MM patients compared to controls and in increased disease stages. They all also significantly decreased in plateau phase. IL-8 correlated positively with Ang and PDGF-AB, but not with MVD. The circulating levels of IL-8, PDGF-AB and Ang are elevated in patients with MM. The lack of correlation between IL-8 with MVD suggests that its levels represent the inflammatory element of MM disease and the participation in angiogenesis process is rather complex with multifactorial mechanisms.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Bone Marrow; Female; Humans; Interleukin-8; Linear Models; Male; Microvessels; Middle Aged; Multiple Myeloma; Neovascularization, Pathologic; Ribonuclease, Pancreatic; Statistics, Nonparametric

Angiogenesis is an essential process for the expansion of multiple myeloma (MM), in which many angiogenic factors participate. Endoglin (CD105) is a transforming growth factor-β co-receptor, being mainly expressed in angiogenic endothelial cells and has been used as a marker of tumor angiogenesis, having prognostic potential. The aim of the study was to evaluate serum levels of soluble CD105 (sCD105) in MM patients, both during diagnosis and after effective conventional chemotherapy, in the plateau phase, and to correlate them with the clinical stage of the disease, as well as with the known angiogenic factors vascular endothelial growth factor, angiogenin and interleukin-18 (IL-18). Serum levels of the aforementioned factors were measured, by enzyme-linked immunosorbent assay, in 56 newly diagnosed MM patients, in 35 of them who entered plateau phase and in 24 healthy controls. Bone marrow aspirations were also performed in all patients to determine plasma cell infiltration. All measured cytokines were higher in MM patients compared with controls and with advancing disease stage (p < 0.001 for all cases). Furthermore, the values of all factors decreased significantly in the plateau phase (p < 0.001 for all cases). Serum levels of sCD105 correlated with the other angiogenic cytokines, whereas only serum levels of angiogenin had prognostic value for the survival. In conclusion, CD105 and the angiogenic cytokines vascular endothelial growth factor, angiogenin and IL-18, seem to have emerging roles both in angiogenesis and tumor growth in MM.

Topics: Adult; Aged; Aged, 80 and over; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Disease Progression; Endoglin; Female; Humans; Interleukin-18; Kaplan-Meier Estimate; Male; Middle Aged; Multiple Myeloma; Neoplasm Proteins; Neovascularization, Pathologic; Prognosis; Receptors, Cell Surface; Ribonuclease, Pancreatic; Vascular Endothelial Growth Factor A

Symptomatic multiple myeloma (MM) evolves from an asymptomatic precursor state termed monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). Angiogenesis plays a key role in the pathogenesis of MM but there are very limited data for angiogenesis in SMM.. We measured the circulating levels of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), and angiogenin in 54 patients with SMM. The results were compared with those of 27 MGUS patients, 55 MM patients, and 22 healthy controls. The expression of VEGF-A gene was also evaluated in 10 patients with SMM, 10 with symptomatic MM, and 10 with MGUS.. The ratio of circulating Ang-1/Ang-2 was reduced in MM patients with symptomatic disease due to a dramatic increase of Ang-2 (p<0.001), but not in patients with SMM or MGUS, in whom it did not differ compared to controls. VEGF and angiogenin were increased in all patients compared to controls. However, circulating VEGF was higher in symptomatic MM compared to SMM and MGUS, while angiogenin was reduced. There were no differences in the expression of VEGF-A among the 3 patients categories.. SMM has a circulating angiogenic cytokine profile similar to that of MGUS, but has altered profile compared to symptomatic MM. Thus, in the progression of MGUS to SMM, circulating angiogenic cytokines seem to be the same. On the contrary, in symptomatic myeloma, the alterations of angiopoietins along with VEGF contribute to myeloma cell growth, supporting the target of these molecules for the development of novel anti-myeloma agents.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inducing Agents; Angiopoietin-1; Angiopoietin-2; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma; Neovascularization, Pathologic; Ribonuclease, Pancreatic; Statistics, Nonparametric; Vascular Endothelial Growth Factor A

Angiogenesis is a complex process essential for the growth, invasion, and metastasis of various malignant tumours, including multiple myeloma (MM). Various angiogenic cytokines have been implicated in the angiogenic process. Among them, platelet-derived growth factor-AB (PDGF-AB) has been reported to be a potent stimulator of angiogenesis in many solid tumours and haematological malignancies, including MM. The aim of the study was to investigate the relationship between PDGF-AB, microvascular density (MVD), and various angiogenic cytokines, such as basic fibroblast growth factor (b-FGF), angiogenin (ANG), and interleukin-6 (IL-6), in MM patients. Forty-seven MM patients before treatment, 22 of whom were in plateau phase, were studied. We determined the serum levels of the aforementioned cytokines and MVD in bone marrow biopsies before and after treatment. Mean serum values of PDGF-AB, b-FGF, ANG, and MVD were significantly higher in patients compared with controls and with increasing disease stage. Significant positive correlations were observed between serum PDGF-AB, ANG, and IL-6 levels and MVD. Furthermore, we found significant positive correlations between PDGF-AB and b-FGF, IL-6, ANG, and β2 microglobulin. We also found that patients with high MVD had statistically significantly higher serum levels of PDGF-AB when a median MVD value of 7.7 was used as the cutoff point. Furthermore, a significant difference was found in serum levels of PDGF-AB between pre- and post-treatment patients. Finally, survival time was significantly higher in the low MVD group versus the high MVD group (76 vs 51 months). Our results showed that there is a strong positive correlation between PDGF-AB and the studied angiogenic cytokines and MVD. It seems that PDGF-AB plays a role in the complex network of cytokines inducing bone marrow neovascularization in patients with MM.

Topics: Adult; Aged; Aged, 80 and over; beta 2-Microglobulin; Bone Marrow; Disease Progression; Female; Fibroblast Growth Factor 2; Humans; Interleukin-6; Male; Microvessels; Middle Aged; Multiple Myeloma; Neoplasm Proteins; Neovascularization, Pathologic; Platelet-Derived Growth Factor; Ribonuclease, Pancreatic

Serum levels of five angiogenic cytokines were evaluated in 82 patients with primary systemic amyloidosis (AL). Angiopoietin-1, vascular endothelial growth factor, basic fibroblast growth factor and angiogenin were higher in AL patients than in controls (n = 35) and newly-diagnosed, symptomatic, myeloma patients (n = 35). Angiopoetin-1/Angiopoetin-2 ratio was lower in AL compared to controls but higher than in myeloma patients. Angiopoetin-2 correlated with cardiac dysfunction indices; however, none of the angiogenic growth factors was prognostically significant. The increased angiogenic cytokine levels observed in AL seem to represent either a toxic effect of amyloid fibrils or light chains, or a compensatory response to organ dysfunction.

Topics: Adult; Aged; Aged, 80 and over; Amyloidosis; Angiogenic Proteins; Angiopoietin-1; Biomarkers; Fibroblast Growth Factor 2; Humans; Middle Aged; Multiple Myeloma; Neoplasm Proteins; Ribonuclease, Pancreatic; Vascular Endothelial Growth Factor A

ImmunoRNases represent a highly attractive alternative to conventional immunotoxins for cancer therapy. Quantitative production of immunoRNases in appropriate expression systems, however, remains a major challenge for further clinical development of these novel compounds. Here we describe a method for high-level production and purification of a fully functional immunoRNase fusion protein from supernatants of stably transfected mammalian cells.

Topics: Animals; Cell Death; Cell Line, Tumor; Clone Cells; Drug Screening Assays, Antitumor; Flow Cytometry; Genetic Vectors; Humans; Immunoglobulin Variable Region; Mice; Molecular Biology; Multiple Myeloma; Recombinant Fusion Proteins; Ribonuclease, Pancreatic; Sialic Acid Binding Ig-like Lectin 2; Transfection

Topics: Adult; Aged; Antineoplastic Agents; Boronic Acids; Bortezomib; Female; Humans; Male; Microcirculation; Middle Aged; Multiple Myeloma; Neovascularization, Pathologic; Protease Inhibitors; Pyrazines; Ribonuclease, Pancreatic; Vascular Endothelial Growth Factor A

Interleukin-18 (IL-18) plays a role in the host's response to tumours and angiogenesis. We determined serum levels of IL-18, vascular endothelial growth factor (VEGF), angiogenin (ANG), tumor necrosis factor (TNF-alpha) and CRP in 65 newly diagnosed myeloma patients. IL-18, VEGF, angiogenin, TNF-alpha and CRP were significantly higher at stage III in comparison to stages II and I. These cytokines (measured in 27 patients) significantly decreased after treatment. In survival analysis, higher levels of IL-18 were associated with a poorer prognosis. We conclude that increased serum IL-18 in myeloma patients correlates with advanced disease, increased levels of angiogenic cytokines and worse survival.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; C-Reactive Protein; Dexamethasone; Disease Progression; Doxorubicin; Female; Humans; Interleukin-18; Life Tables; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Proteins; Prednisone; Prospective Studies; Ribonuclease, Pancreatic; Survival Analysis; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Vincristine

Topics: Aged; Biomarkers; Female; Humans; Male; Middle Aged; Multiple Myeloma; Neoplasm Staging; Reference Values; Ribonuclease, Pancreatic