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ABSTRACT: Heat shock protein 90 (HSP90) binds and stabilizes numerous proteins and kinases essential for myeloma cell survival and proliferation. We and others have recently demonstrated that inhibition of HSP90 by small molecular mass inhibitors induces cell death in multiple myeloma (MM). However, some of the HSP90 inhibitors involved in early clinical trials have shown limited antitumor activity and unfavorable toxicity profiles. Here, we analyzed the effects of the novel, orally bioavailable HSP90 inhibitor NVP-HSP990 on MM cell proliferation and survival. The inhibitor led to a significant reduction in myeloma cell viability and induced G2 cell cycle arrest, degradation of caspases-8 and -3 and induction of apoptosis. Inhibition of the HSP90 ATPase activity was accompanied by degradation of MM phospho-Akt and phospho-ERK1/2 and upregulation of Hsp70. Exposure of MM cells to a combination of NVP-HSP990 and either melphalan or histone deacetylase (HDAC) inhibitors caused synergistic inhibition of viability, increased induction of apoptosis and was able to overcome the primary resistance of the cell line RPMI-8226 to HSP90 inhibition. Combined incubation with melphalan and NVP-HSP990 led to synergistically increased cleavage of caspases-2, -9 and -3. These data demonstrate promising activity for NVP-HSP990 as single agent or combination treatment in MM and provide a rationale for clinical trials. (c) 2012 John Wiley & Sons A/S.
European Journal Of Haematology 02/2012; · 2.61 Impact Factor
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L Kleeberg,
Stanislao Morgera,
C Jakob,
B Hocher,
M Schneider,
H Peters,
S Rötzer,
C Müller,
M Kaiser,
C Fleissner, U Heider,
H-H Neumayer,
O Sezer
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ABSTRACT: Multiple myeloma (MM) is a malignancy with excessive production of monoclonal proteins. At disease presentation 30% of MM patients have significant renal impairment which may progress to renal failure requiring dialysis. Besides chemotherapy extracorporeal elimination procedures such as plasma exchange have been applied as adjuvant strategies to eliminate free light chains from circulating blood, however the efficacy was poor with older techniques. We report about a highly efficient method to eliminate serum free light chain (sFLC) using a newly designed protein leaking membrane in patients suffering from sFLC induced acute renal failure. The protein leaking membrane (HCO 1100) is characterized by increased pore size facilitating elimination of middle molecules such as sFLC kappa (22.5 kD). The HCO 1100 membrane was applied in a hemodialysis and hemodiafiltration mode and compared to standard procedures (high flux hemodialysis, hemodiafiltration and plasma exchange). Hemodiafiltration with the protein leaking membrane HCO 1100 was superior to all other extracorporeal replacement strategies in eliminating sFLC-kappa from circulating blood. A median blood reduction rate of 40.8% (range 13.9% - 66.4%) was achieved during hemodiafiltration. The corresponding peak clearance rate was 25 ml/min. Importantly, the poorest elimination rate was achieved by plasma exchange followed by standard high flux hemodialysis. Extracorporeal elimination strategies with the protein leaking membrane HCO 1100 may be a promising adjuvant treatment strategy for patients with sFLC nephropathy requiring dialysis. Hemodiafiltration and to lesser extend also hemodialysis with the HCO 1100 hemofilter are able to eliminate substantial amounts of sFLC kappa in MM patients.
European journal of medical research. 03/2009; 14(2):47-54.
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C Jakob,
J Sterz,
P Liebisch,
M Mieth,
J Rademacher,
A Goerke, U Heider,
C Fleissner,
M Kaiser,
I von Metzler,
C Müller,
O Sezer
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2008; 22(9):1812. · 8.30 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2008; 22(12):2273-7. · 8.30 Impact Factor
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A K|[uuml]|hne,
O Sezer, U Heider,
I Meineke,
S Muhlke,
W Niere,
T Overbeck,
K Hohloch,
L Tr|[uuml]|mper,
J Brockm|[ouml]|ller,
R Kaiser
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ABSTRACT: Melphalan is associated with severe side effects such as mucositis, diarrhea, and myelosuppression. We investigated how much the individual severity of these side effects is predicted by pharmacokinetics. In addition, we studied glutathione S-transferase GSTM1, GSTT1, and GSTP1 polymorphisms in relation to adverse events. A high interindividual pharmacokinetic variability was observed in 84 patients. There was a linear correlation between creatinine and melphalan clearance (P=0.0004). Patients treated with a dose 70 mg/m2 had a 23-fold increased risk to develop mucositis (P<0.001) and a 12-fold increased risk to develop diarrhea (P<0.001) compared with lower doses. The GSTP1 codon 105 polymorphism may be relevant for development of mucositis and the GSTT1 deletion may predict diarrhea, but these findings require confirmation. Melphalan-induced side effects were significantly dependent only on dose. Therapeutic drug monitoring or genotyping for GST does not appear to be very helpful in optimizing therapy with melphalan.
Clinical Pharmacology & Therapeutics 10/2007; 83(5):749-757. · 6.04 Impact Factor
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I von Metzler,
H Krebbel,
M Hecht,
R A Manz,
C Fleissner,
M Mieth,
M Kaiser,
C Jakob,
J Sterz,
L Kleeberg, U Heider,
O Sezer
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ABSTRACT: In multiple myeloma, the overexpression of receptor activator of nuclear factor kappa B (NF-kappaB) ligand (RANKL) leads to the induction of NF-kappaB and activator protein-1 (AP-1)-related osteoclast activation and enhanced bone resorption. The purpose of this study was to examine the molecular and functional effects of proteasome inhibition in RANKL-induced osteoclastogenesis. Furthermore, we aimed to compare the outcome of proteasome versus selective NF-kappaB inhibition using bortezomib (PS-341) and I-kappaB kinase inhibitor PS-1145. Primary human osteoclasts were derived from CD14+ precursors in presence of RANKL and macrophage colony-stimulating factor (M-CSF). Both bortezomib and PS-1145 inhibited osteoclast differentiation in a dose- and time-dependent manner and furthermore, the bone resorption activity of osteoclasts. The mechanisms of action involved in early osteoclast differentiation were found to be related to the inhibition of p38 mitogen-activated protein kinase pathways, whereas the later phase of differentiation and activation occurred due to inhibition of p38, AP-1 and NF-kappaB activation. The AP-1 blockade contributed to significant reduction of osteoclastic vascular endothelial growth factor production. In conclusion, our data demonstrate that proteasomal inhibition should be considered as a novel therapeutic option of cancer-induced lytic bone disease.
Leukemia 10/2007; 21(9):2025-34. · 9.56 Impact Factor
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ABSTRACT: The 26S proteasome is a multicatalytic intracellular protease expressed in eukaryotic cells. It is responsible for selective degradation of intracellular proteins that are responsible for cell proliferation, growth, regulation of apoptosis and transcription of genes involved in execution of key cellular functions. Thus proteasome inhibition is a potential treatment option for cancer and diseases due to aberrant inflammation condition. Treatment with proteasome inhibitors results in stabilization and accumulation proteasome substrates, a phenomenon that may result in confounding signals in cells, cell cycle arrest and activation of apoptotic programs. The inhibition of the transcriptional factor nuclear factor kappaB (NF-kappaB) activation was found as one of crucial mechanisms in induction of apoptosis, overcoming resistance mechanisms and inhibition of immune response and inflammation mechanisms. Bortezomib (PS-341) and PS-519 are the first proteasome inhibitors that have entered clinical trials. In multiple myeloma, both the FDA (United States Food and Drug Administration) and EMEA (European Medicine Evaluation Agency) granted an approval for the use of bortezomib (Velcade) for the treatment of relapsed multiple myeloma. At present, several phase II and phase III trials in hematological malignancies and solid tumors are ongoing. PS-519 that focuses on inflammation, reperfusion injury and ischemia is currently under evaluation for the indication of acute stroke.
Current pharmaceutical design 02/2007; 13(5):471-85. · 4.41 Impact Factor
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ABSTRACT: Cyclophosphamide (CP), a widely used cytostatic, is metabolized by polymorphic drug metabolizing enzymes particularly cytochrome P450 (CYP) enzymes. Its side effects and clinical efficacy exhibit a broad interindividual variability, which might be due to differences in pharmacokinetics. CP-kinetics were determined in 60 patients using a global and a population pharmacokinetic model considering functionally relevant polymorphisms of CYP2B6, CYP2C9, CYP2C19, CYP3A5, and GSTA1. Moreover, metabolic ratios were calculated for selected CP metabolites, analyzed by (31)P-NMR-spectroscopy. Analysis of variance revealed that the CYP2C19*2 genotype influenced significantly pharmacokinetics of CP at doses </=1000 mg/m(2), whereas there was no evidence of an association of other genotypes to CP elimination or clearance. Mean (+/-SD) CP elimination constants k(e) (h(-1)) were 0.109+/-0.025 in 44 CYP2C19*1/*1 subjects, 0.088+/-0.018 in 13 CYP2C19*1/*2, and 0.076+/-0.014 in three inactive CYP2C19*2/*2 carriers (P=0.009). At CP doses higher than 1000 mg/m(2), a significantly increase of elimination was observed (P=0.001), possibly due to CYP induction. Further studies should link these findings with the clinical outcome.
The Pharmacogenomics Journal 01/2005; 5(6):365-73. · 4.54 Impact Factor
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ABSTRACT: Das Proteasom ist die wichtigste
extralysosomale Protease der Zelle und ist an der
posttranskriptionellen Regulation einer groen Anzahl von
Proteinen beteiligt, die fr die Zellzykluskontrolle,
Zelldifferenzierung, Zellproliferation und Apoptose von
mageblicher Bedeutung sind. Die Hemmung der Proteasom-
Aktivitt fhrt bei einer Reihe von humanen Tumorzelllinien zur
Wachstumshemmung und Apoptose, sodass daraus ein neues
Wirkprinzip in der Krebstherapie entstanden ist. Als erster
Vertreter dieser neuen Klasse von Krebstherapeutika wurde das
Boronsuredipeptid Bortezomib (frhere Bezeichnung PS-341) in
die Klinik eingefhrt. Bortezomib
(Velcade
)
wurde im Mai 2003 in den USA fr die Therapie des rezidivierten/
refraktren multiplen Myeloms zugelassen. Die wichtigsten
Nebenwirkungen sind Thrombozytopenie, periphere Neuropathie,
Mdigkeit und Neutropenie. Zurzeit wird die Wirksamkeit dieser
Substanz in der Monotherapie und in Kombination mit anderen
Medikamenten nicht nur beim multiplen Myelom, sondern auch bei
einer Reihe von anderen malignen Erkrankungen
evaluiert.
Der Onkologe 09/2003; 9(10):1102-1107. · 0.17 Impact Factor
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ABSTRACT: HMGI-C belongs to the high-mobility-group-protein (HMG) family of architectural transcription factors and considerable interest has recently been shown in its expression in neoplastic tissues and apparent involvement in tumorigenesis. We could previously demonstrate an expression of HMGI-C mRNA in the peripheral blood of breast cancer patients for the first time. In this prospective study, we evaluated the independent prognostic power of HMGI-C mRNA expression in the peripheral blood of an unselected cohort of 69 patients with metastatic breast cancer using a hemi-nested reverse transcriptase polymerase chain reaction (RT-PCR) followed by sequence analysis of the resulting PCR products. Multivariate analysis was performed using the Cox regression model. HMGI-C mRNA was detected in peripheral blood from 21 out of 69 (30%) patients with metastatic breast cancer. Median survival was 15.9 months in patients expressing HMGI-C, while in the group of patients without HMGI-C expression the median survival had not been reached yet after a median follow-up of 24.7 months and 85.4% were still alive in this group. Disease-specific survival was significantly worse for patients positive for HMGI-C in comparison to those not expressing HMGI-C (P=0.0001). In a multivariate regression analysis, HMGI-C remained an independent prognostic factor for overall survival (P=0.001) besides oestrogen receptor status (P=0.024) and presence of metastases in liver and lungs (P=0.029). HMGI-C expression in the peripheral blood of patients with metastatic breast cancer is a powerful independent indicator for poor overall survival and this is the first study to demonstrate its prognostic relevance in univariate and multivariate analysis.
British Journal of Cancer 06/2003; 88(9):1406-10. · 5.04 Impact Factor
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ABSTRACT: There is growing evidence that angiogenesis is important not only in solid tumors but also in hematological malignancies. Recently, we found that bone marrow angiogenesis is a prognostic factor for disease-related survival in patients with multiple myeloma. In this report, we addressed the question of whether the microvessel density in bone marrow biopsies is correlated to other myeloma parameters, e.g., serum beta2-microglobulin (beta2-MG) and plasma cell infiltration in the bone marrow. In 22 multiple myeloma patients, immunohistochemical, CD34-stained, paraffin-embedded bone marrow biopsies before and after chemotherapy were studied. Microvessels were counted in 400x magnification, and the mean number of vessels per area in each sample was noted as the microvessel density (MVD). Pretreatment bone marrow MVD (median: 44, range: 11-175 vessels/mm2) correlated significantly with the bone marrow plasma cell infiltration (median: 30%, range: 5-90%, r = 0.642, P=0.001) and beta2-MG (median: 2.74, range: 1.4-26.1 mg/l, r = 0.749, P < 0.0005). In contrast, there was no correlation between posttreatment MVD and plasma cell infiltration or beta2-MG (median: MVD 31, range: 0-221 vessels/mm2, median plasma cell infiltration: 15%, range: 5-80%, r = 0.229, P = 0.306 and median beta2-MG: 2.65, range: 1-27.6 mg/l, r = -0.042, P = 0.853). These findings show that the strong correlations between bone marrow MVD and plasma cell infiltration as well as serum beta2-MG levels disappear after chemotherapy. The underlying mechanisms need further investigations.
Annals of Hematology 10/2001; 80(10):598-601. · 2.62 Impact Factor
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ABSTRACT: The differential diagnosis between multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) may be uncertain in some cases; this problem is reflected by discrepancies between different classification systems with an accordance in only 2/3 of cases. We studied whether flow-cytometric characteristics of plasma cells (PC) can be used for the differentiation between MGUS and MM.
Patients were divided into 3 groups: Group A included 13 myeloma patients with a plasma cell infiltration of the bone marrow of 10-30%, serum M-protein < or = 3.5 g/dL (IgG) or < or = 2 g/dl (IgA) and without bone lesions in conventional radiography. Group B consisted of 53 patients who fulfilled the Durie and Salmon diagnostic criteria including at least one major criterion, and group C individuals with MGUS (n=17). The ratio of immunophenotypically normal (i.e. CD19(+)/CD56(-)) to all bone marrow plasma cells (BMPC), the number of peripheral blood PC (PBPC), the percentage of BMPC in S-phase and the DNA content of BMPC were analyzed.
All individuals with MGUS and no patient with MM in group A or group B had a ratio of phenotypically normal to all BMPC > or = 20%. The median of monoclonal PBPC was 0/microL (range 0-2/ microL) in MGUS, 1/microL (range 0-30/microL) in MM group A and 2.4/microL (range 0-211/microL) in MM group B. The median percentage of BMPC in S-phase was 1.6% both in MGUS and in group A and 3% in group B. Aneuploidy was found in 12%, 11% and 41% in MGUS, group A and group B, respectively.
The ratio of immunophenotypically normal to all BMPC was the only flow-cytometric parameter for the differentiation of MGUS and MM group A (p<0.0005). The other parameters were significantly different between MGUS and MM group B, but not group A.
Haematologica 09/2001; 86(8):837-43. · 6.42 Impact Factor
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ABSTRACT: In a patient with nephrotic syndrome, renal biopsy revealed AL amyloid deposits. Monoclonal lambda light chains were identified in serum and urine. A low percentage of monoclonal plasma cells was detected in the bone marrow. The patient received four cycles of VAD and subsequent high-dose chemotherapy (HDCT) with melphalan (200 mg/m2) followed by autologous peripheral blood stem cell transplantation. Proteinuria rapidly diminished during chemotherapy. Three months after HDCT, the patient has no edema, and no signs of plasma cell dyscrasia are currently detectable. Using VAD before starting HDCT may improve the condition of patients with amyloidosis and reduce transplantation-related morbidity and mortality.
Bone Marrow Transplantation 06/1999; 23(9):967-9. · 3.75 Impact Factor
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ABSTRACT: We developed a piezoelectric scanner for probe microscopes that uses only single‐domain LiNbO 3 crystals as a piezoelectric transducer material in order to avoid nonlinearity, hysteresis, and creep that is always present in piezoelectric ceramics. A raster area of about 50×50 nm<sup>2</sup> is within reach of a scanner that uses three double‐plate translators and a scanning voltage of 300 V peak to peak. The performance of monocrystal scanners for investigations in the range of atomic resolution is demonstrated by imaging the well‐known surface of highly oriented pyrolytic graphite.
Review of Scientific Instruments 01/1994; · 1.37 Impact Factor
