Search PubMed⌕ Search

Biomedical subjects

B Dörken

Publications and source records attributed to B Dörken.

At least 19 recordsLinked to original sources
PubMed2006

Initial chemotherapy with mitoxantrone, chlorambucil, prednisone impairs the collection of stem cells in patients with indolent lymphomas--results of a randomized comparison by the German Low-Grade Lymphoma Study Group.

Myeloablative radio-chemotherapy with subsequent autologous stem cell transplantation (ASCT) significantly prolongs progression free and probably overall survival in follicular lymphoma (FL) in first remission. The current trial explored prospectively the rate of successful stem cell mobilization in patients with advanced stage FL after initial therapy with either Mitoxantrone, Chlorambucil, Prednisone (MCP) or Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP) as part of a prospective randomized comparison of both regimens. ASCT patients received Dexa-BEAM (Dexamethasone, BCNU, Melphalan, Etoposide, Cytarabine) for mobilization of stem cells. Stem cells were collected and a minimum of 2x2.0x106/kg bw CD34+ was required for ASCT. Of 79 evaluable patients, 58 (73%) had follicular lymphoma, 13 (16%) mantle cell lymphoma and 8 (10%) lymphoplasmacytic lymphoma. In the 45 patients assigned to CHOP, stem cell collection was successful in 42 cases (93%, 95% CI 82% to 99%). This high mobilization rate after CHOP could be confirmed in 61 subsequent patients (87%). In contrast, after MCP therapy stem cell collection was successful in only 15 of 34 patients (44%, 95% CI 27% to 62%; P=0.0003). In conclusion, initial therapy with MCP significantly impairs the ability to collect stem cells and should be avoided for first line therapy of younger patients potentially qualifying for high dose consolidation and ASCT in first remission.

Adult↗
PubMed2006

Bak functionally complements for loss of Bax during p14ARF-induced mitochondrial apoptosis in human cancer cells.

In contrast to the initial notion that the biological activity of p14(ARF) strictly depends on a functional mdm-2/p53 signaling axis, we recently demonstrated that p14(ARF) mediates apoptosis in a p53/Bax-independent manner. Here, we show that p14(ARF) induces breakdown of the mitochondrial membrane potential and cytochrome c release before triggering caspase-9- and caspase-3/7-like activities in p53/Bax-deficient DU145 prostate cancer cells expressing wild-type Bak. Re-expression of Bax in these cells failed to further enhance p14(ARF)-induced apoptosis, suggesting that p14(ARF)-induced apoptosis primarily depends on Bak but not Bax in these cells. To further define the role of Bak and Bax in p14(ARF)-induced mitochondrial apoptosis, we employed short interference RNA for the knockdown of bak in isogeneic, p53 wild-type HCT116 colon cancer cells either proficient or deficient for Bax. There, combined loss of Bax and Bak attenuated p14(ARF)-induced apoptosis whereas single loss of Bax or Bak was only marginally effective, as in the case of DU145. Notably, HCT116 cells deficient for Bax and Bak failed to release cytochrome c and showed attenuated activation of caspase-9 (LEHDase) and caspase-3/caspase-7 (DEVDase) upon p14(ARF) expression. These data indicate that p14(ARF) triggers apoptosis via a Bax/Bak-dependent pathway in p53-proficient HCT116, whereas Bax is dispensable in p53-deficient DU145 cells. Nevertheless, a substantial proportion of p14(ARF)-induced cell death proceeds in a Bax/Bak-independent manner. This is also the case for inhibition of clonogenic growth that occurs, at least in part, through an entirely Bax/Bak-independent mechanism.

Apoptosis↗
PubMed2006

Induction of p21CIP/WAF-1 and G2 arrest by ionizing irradiation impedes caspase-3-mediated apoptosis in human carcinoma cells.

There is an ongoing controversy regarding the relevance of apoptosis induction by ionizing irradiation as compared with other end points including transient or permanent cell cycle arrest of damaged cells. Here, we show that such permanent cell cycle arrest and apoptosis represent two sides of the same coin. MCF-7 cells fail to express procaspase-3, which results in resistance to apoptosis induced by anticancer drugs. Conversely, restoration of procaspase-3 sensitizes MCF-7 cells to chemotherapeutics including epirubicine, etoposide and taxol. In contrast, irradiation does not trigger apoptotic cell death but results in prolonged arrest in the G2 phase of the cell division cycle regardless of procaspase-3 expression. This suggested that the propensity of MCF-7 cells to arrest at the G2 checkpoint results in resistance to apoptosis upon gamma-irradiation. This G2 arrest was associated with upregulation of p21CIP/WAF-1. Inhibition of DNA-damage-induced stress kinases and p21CIP/WAF-1 expression by caffeine abrogated G2 arrest and induced apoptosis of the irradiated cells in a caspase-3-dependent manner. Inhibition of cell cycle progression by adenoviral expression of the cyclin dependent kinase inhibitor p21CIP/WAF-1 prevented apoptosis upon caffeine treatment indicating that cell cycle progression, that is, G2-release, is required for induction of apoptosis. Likewise, cells homozygously deleted for p21CIP/WAF-1 (HCT116 p21-/-) display enhanced irradiation-induced apoptosis via a caspase-3-dependent mechanism. These data indicate that the disruption of G2 checkpoint control overcomes cell cycle arrest and resistance to gamma-irradiation-induced cell death. Thus, DNA damage may trigger a permanent G2 arrest as an initial inactivation step of tumor cells where the phenomenon of apoptosis is hidden unless cell cycle arrest is overcome. The efficient induction of apoptosis upon G2 release thereby depends on the propensity to activate the key executioner caspase-3. This finding is of crucial importance for the understanding of molecular steps underlying the efficacy of ionizing radiation to delete tumor cells.

Antineoplastic Agents↗
PubMed2006

Loss of the tissue-specific proapoptotic BH3-only protein Nbk/Bik is a unifying feature of renal cell carcinoma.

We report for the first time inactivation of a tissue-specific Bcl-2 homology domain 3 (BH3)-only protein as a common aspect in human cancer. In detail, we show that loss of the BH3-only protein natural born killer (Nbk)/Bcl-2-interacting killer (Bik) is a common feature of clear-cell renal cell carcinoma (RCC). While strong Nbk expression is found in the renal tubuli and the epithelial lining of the glomerula, a consistent loss of Nbk expression was observed in primary RCC tissue and RCC cell lines. Mutation of Nbk is, however, rare, whereas deletion of the Nbk gene at 22q13.2 is frequent. In addition to loss of heterozygosity (LOH), DNA methylation mediates transcriptional silencing of the Nbk gene. The conditional restoration of Nbk/Bik expression led to apoptotic death of RCC but not of nonmalignant renal epithelia. A broader expression analysis of RCC cell lines for BH3-only proteins revealed that loss of Nbk coincides with failure to express Bim, whereas Puma, Bid and BNIP3 are readily detectable and, in case of Puma, inducible by p53. These data delineate a role for defects in BH3-only proteins as tumor suppressors in RCC and may explain at the same time the impressive clinical apoptosis resistance of RCC.

Adult↗
PubMed2005

High-dose sequential chemotherapy followed by autologous stem cell transplantation in relapsed and refractory aggressive non-Hodgkin's lymphoma: results of a multicenter phase II study.

BACKGROUND: Combination chemotherapy can cure patients with non-Hodgkin's lymphoma (NHL), but those who suffer treatment failure or relapse still have a poor prognosis. High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) can improve the outcome of these patients. We evaluated an intensified high-dose sequential chemotherapy program with a final myeloablative course. PATIENTS AND METHODS: Inclusion criteria were age 18-65 years, histologically proven primary progressive or relapsed aggressive NHL and eligibility for HDCT. The therapy consists of two cycles DHAP: dexamethasone 40 mg (day 1-4), high-dose cytarabine 2 g/m2 12q (day 2), cisplatin 100 mg/m2 (day 51); patients with partial (PR) or complete remission (CR) received cyclophosphamide 4 g/m2 (day 37), followed by peripheral blood stem cell (PBSC) harvest; methotrexate 8 g/m2 (day 1) plus vincristine 1.4 mg/m2 (day 51); and etoposide 500 mg/m2 (day 58-62). The final myeloblative course was BEAM: cytarabine 200 mg/m2 12q (day 81-84), etoposide 150 mg/m2 12q (day 81-84), melphalan 140 mg/m2 (day 80), carmustin 300 mg/m2 (day 80) followed by PBSCT. RESULTS: Fifty-seven patients (median age 43 years, range 24-65) were enrolled: 23 (40%) patients were refractory to primary therapy and 34 (60%) patients had relapsed NHL. The response rate (RR) after 2 cycles of DHAP was 72% (9% CR, 63% PR) and at the final evaluation (100 days post transplantation) 43% (32% CR, 11% PR). Toxicity was tolerable. Median follow-up was 25 months (range 1-76 months). Freedom from second failure (FF2F) and overall survival (OS) at 2 years were 25% and 47% for all patients, respectively. FF2F at 2 years for patients with relapse and for patients refractory to primary therapy were 35% and 9% (P=0.0006), respectively. OS at 2 years for patients with relapse and for patients refractory to primary therapy were 58% and 24% (P=0.0044), respectively. CONCLUSIONS: We conclude that this regimen is feasible, tolerable and effective in patients with relapsed NHL. In contrast, the results in patients with progressive disease are unsatisfactory. This program is currently being modified by addition of rituximab for patients with relapsed aggressive NHL.

Adolescent↗
PubMed2005

[Basics of molecular diagnostics and therapy of malignant tumors].

Recent insights in disease pathogenesis and mechanisms of resistance to therapy of malignant tumors provide a rational basis for the development of novel therapeutic strategies that target genetic defects and deregulated signaling events in malignant tumors. In contrast to conventional therapeutics, small molecule inhibitors or monoclonal antibodies allow for a far more selective, targeted therapy of tumors that carry a corresponding target structure or gene expression profile. Molecular therapeutics therefore necessitate clinical deployment of genetic diagnostics for the identification of those patients who have a chance to benefit from these novel targeted therapies.

Animals↗
PubMed2005

Survival after reduced-intensity conditioning is not inferior to standard high-dose conditioning before allogeneic haematopoietic cell transplantation in acute leukaemias.

To assess the role of allogeneic stem cell transplantation (SCT) after reduced-intensity conditioning (RIC) in acute leukaemias, we retrospectively compared 25 patients with acute lymphoblastic leukaemia or acute myelogenous leukaemia after RIC to a historical group of 50 matched controls after high-dose conditioning. Engraftment, acute GvHD and severe infections were comparable in both groups. During the observation period, 1/25 patients (4%) after RIC and 14/50 (28%) after standard SCT died due to transplant-related causes; cumulative nonrelapse mortality (NRM) was 4% after RIC and 24% after standard SCT (P=0.029). In total, 15/25 patients (60%) relapsed after RIC and 20/50 (40%) after standard SCT; probability of disease-free survival (DFS) at 3 years was 43% after RIC and 49% after standard SCT (NS). Overall survival (OS) was 40% after RIC and 37% after standard SCT (NS). Stage of disease, cytogenetic risk profile, acute and chronic GvHD, chimerism status at day 90 and severe infections after transplantation were risk factors with significant impact on DFS and/or OS. In retrospective analysis, patients with acute leukaemias who receive RIC because of contraindications against standard SCT have a comparable outcome to standard SCT, but the higher relapse rate warrants further studies.

Acute Disease↗
PubMed2005

Induction of gene expression by 5-Aza-2'-deoxycytidine in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) but not epithelial cells by DNA-methylation-dependent and -independent mechanisms.

The methylation inhibitor 5-Aza-2'-deoxycytidine (5-Aza-CdR, decitabine) has therapeutic efficacy in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Using microarray analysis, we investigated global changes in gene expression after 5-Aza-CdR treatment in AML. In the AML cell line OCI-AML2, Aza-CdR induced the expression of 81 out of 22 000 genes; 96 genes were downregulated (> or =2-fold change in expression). RT-PCR analysis of 10 randomly selected genes confirmed the changes of expression in AML cells. Similar results were obtained with primary AML and MDS cells after treatment with 5-Aza-CdR ex vivo and in vivo, respectively. In contrast, significantly fewer changes in gene expression and cytotoxicity were detected in normal peripheral blood mononuclear and bone marrow cells or transformed epithelial cells treated with 5-Aza-CdR. Interestingly, only 50.6% of the induced genes contain putative CpG islands in the 5' region. To further investigate the significance of promoter methylation in the induced genes, we analyzed the actual methylation status of randomly selected 5-Aza-CdR-inducible genes. We detected hypermethylation exclusively in the 5' region of the myeloperoxidase (MPO) gene. DNA methylation inversely correlated with MPO expression in newly diagnosed untreated AML patients (P< or =0.004). In contrast, all other analyzed 5-Aza-CdR-inducible genes revealed no CpG methylation in the promoter region, suggesting a methylation-independent effect of 5-Aza-CdR.

Acute Disease↗
PubMed2005

Cologne high-dose sequential chemotherapy in relapsed and refractory Hodgkin lymphoma: results of a large multicenter study of the German Hodgkin Lymphoma Study Group (GHSG).

BACKGROUND: We designed a dose- and time-intensified high-dose sequential chemotherapy regimen for patients with relapsed and refractory Hodgkin lymphoma (HD). PATIENTS AND METHODS: Eligibility criteria included age 18-65 years, histologically proven primary progressive (PD) or relapsed HD. Treatment consisted of two cycles DHAP (dexamethasone, high-dose cytarabine, cisplatinum); patients with chemosensitive disease received cyclophosphamide followed by peripheral blood stem cell harvest; methotrexate plus vincristine, etoposide and BEAM plus peripheral blood stem cell transplantation (PBSCT). RESULTS: A total of 102 patients (median age 34 years, range 18-64) were enrolled. The response rate was 80% (72% complete response, 8% partial response). With a median follow-up of 30 months (range 3-61 months), freedom from second failure (FF2F) and overall survival (OS) were 59% and 78% for all patients, respectively. FF2F and OS for patients with early relapse were 62% and 81%, for late relapse 65% and 81%; for PD 41% and 48%, and for multiple relapse 39% and 48%, respectively. In multivariate analysis response after DHAP (P <0.0001) and duration of first remission (PD and multiple relapse versus early and late relapse; P=0.0127) were prognostic factors for FF2F. Response after DHAP (P <0.0081), duration of first remission (P=0.0017) and anemia (P=0.019) were significant for OS. CONCLUSION: Based on the promising results of this study, a prospective randomized European intergroup study was started comparing this intensified regimen with two courses of DHAP followed by BEAM (HD-R2 protocol).

Adolescent↗
PubMed2005

Effect of anti-CD 20 antibody rituximab in patients with post-transplant lymphoproliferative disorder (PTLD).

Post-transplant lymphoproliferative disorders (PTLD) are a life-threatening complication following solid organ transplantation. Treatment with rituximab, a humanized anti-CD20 monoclonal antibody, has proved to be a promising approach and shown a low toxicity profile. Between February 1999 and April 2002, we conducted a multicentre phase II trial investigating rituximab as single agent in 17 patients with PTLD. Transplanted organs were heart (n = 5), kidney (n = 4), lung (n = 4) and liver (n = 4). Patients were treated with four weekly doses of 375 mg/m(2) of rituximab. The mean follow-up time is 24.2 months. Histology was distributed in 10 diffuse large cell-, 2 marginal zone-, 1 Burkitt-like lymphoma, 1 Hodgkin-like PTLD and 3 polymorphic lymphoproliferations. Therapy was well tolerated and no severe adverse events were observed. The mean overall survival period is 37.0 months with 11 patients still living. In total, 9 patients (52.9%) achieved a complete remission, with a mean duration of 17.8 months. Partial remission was observed in 1 patient, minor remission in 2 patients, no change in 3 patients and 1 patient experienced progressive disease. Two patients relapsed, at intervals 3 and 5 months after obtaining complete remission. Rituximab proved to be well tolerated and effective in the treatment of PTLD.

Adult↗
PubMed2004

Trimethoprim-sulfamethoxazole exacerbates posthypoxic action myoclonus in a patient with suspicion of Pneumocystis jiroveci infection.

We describe a 58-year-old patient with relapsing high-grade non-Hodgkin's lymphoma who exhibited exacerbation of posthypoxic action myoclonus during high-dose intravenous trimethoprim-sulfamethoxazole (TMP-SMX) treatment for highly suspicious Pneumocystis jiroveci pneumonia (PCP). Three months previously the patient had experienced a hypoxic insult caused by respiratory arrest due to an anaphylactic reaction to antibiotic therapy. He had developed posthypoxic action myoclonus (Lance-Adams syndrome), which was well controlled by oral treatment with piracetam. However, after TMP-SMX therapy (115 mg/kg daily) was started for suspicion of newly developed PCP, posthypoxic action myoclonus worsened dramatically resulting in complete disability. Anti-myoclonic therapy with increased doses of piracetam and valproic acid did not significantly improve his clinical condition. Only when TMPSMX doses were reduced (38 mg/kg daily) on day 12 did action myoclonus cease within 2 to 3 days. We suggest that TMP-SMX can exacerbate posthypoxic action myoclonus.

Anti-Infective Agents↗
PubMed2004

Nonmyeloablative stem cell transplantation in metastatic renal cell carcinoma: delayed graft-versus-tumor effect is associated with chimerism conversion but transplantation has high toxicity.

Seven out of 29 patients with metastatic renal cell carcinoma (RCC) considered eligible for allogeneic stem cell transplantation underwent nonmyeloablative stem cell transplantation (NST) from HLA-identical donors. Conditioning comprised cyclophosphamide, fludarabine and antithymocyte globulin. Prolonged mixed chimerism (MC) after engraftment converted to complete donor chimerism (CC) after infusion of donor lymphocytes and/or graft-versus-host disease (GvHD) in six patients. Five patients developed severe GvHD. Two of seven patients had a delayed tumor response after conversion to CC. After a median follow-up of 10 months (4-24 months), 5/7 patients are alive, one in very good partial remission (PR), one with stable and three with progressive disease. One of the seven patients died from sepsis in PR and 1/7 died from rapid tumor progression after sustained MC. None of the 22 nontransplanted patients responded to further therapies. Survival after 1 year was 59% in transplanted and 66% in nontransplanted patients (n.s.). A pooled data analysis from the literature suggests a graft-versus-tumor effect after transplant in patients with metastatic RCC, which becomes effective after chimerism conversion. Available data demonstrate high nonrelapse mortality in these patients. NST in RCC still has to be regarded as an investigational approach requiring careful patients' selection and longer follow-up within clinical studies.

Adult↗
PubMed2004

Flt-3 ligand as adjuvant for DNA vaccination augments immune responses but does not skew TH1/TH2 polarization.

Since transfection of dendritic cells (DC) plays a key role in DNA vaccination, in vivo expansion of DC might be a tool to increase vaccine efficacy. We asked whether Fms-like tyrosine kinase-3 ligand (Flt-3L), a growth factor for DC, can be used as an adjuvant for DNA vaccination. Beta-galactosidase (beta-gal) was used as a model antigen in C57BL/6 mice. Mice were immunized i.m. with DNA coding for beta-gal with or without additional injection of Flt-3L. In both cases, antigen-specific CD4+ and CD8+ T cells were detectable after vaccination. Compared with DNA alone, additional administration of Flt-3L led to a significant increase in the antigen-specific proliferative response. However, increased cytotoxicity by T cells was not observed. The cytokines secreted by splenocytes of immunized mice upon in vitro stimulation with antigen had a TH2 profile. Humoral responses against beta-gal preferentially consisted of IgG1 antibodies. Analysis of DC from Flt-3L-treated mice revealed an immature phenotype with low or absent expression levels of CD80, CD86 and CD40. We conclude that Flt-3L does not generally skew immune responses towards a TH1 type. More likely, factors determined by the antigen and/or the vaccination procedure itself are crucial for the resulting type of immune response. Flt-3L - under circumstances such as the one we have investigated - can also lead to suppression of TH1 T cell immunity, possibly by expansion of immature/unactivated DC.

Adjuvants, Immunologic↗
PubMed2004

A novel recombinant bispecific single-chain antibody, bscWue-1 x CD3, induces T-cell-mediated cytotoxicity towards human multiple myeloma cells.

The development of antibody-based strategies for the treatment of multiple myeloma (MM) has been hampered so far by the fact that suitable plasma cell-specific surface antigens have been missing. However, recently a novel monoclonal antibody, designated Wue-1, has been generated that specifically recognizes normal and malignant human plasma cells. Therefore, Wue-1 is an interesting and promising candidate to develop novel immunotherapeutic strategies for the treatment of MM. One variant for an antibody-based strategy is the bispecific antibody approach. Recombinant bispecific single-chain (bsc) antibodies are especially interesting candidates because they show exceptional biological properties. We have generated a novel MM-directed recombinant bsc antibody, bscWue-1 x CD3, and analyzed the biological properties of this antibody using the MM cell line NCI-H929 and primary cells from the bone marrow of patients with MM. We were able to show that bscWue-1 x CD3 induces efficient and selective T-cell-mediated cell death of NCI-H929 cells and primary myeloma cells in nine out of 11 cases. The bscWue-1 x CD3 Ab is efficacious even at low E:T ratios, and with or without additional T-cell pre- or costimulation. Target cell lyses were specific for Wue-1 antigen-positive cells and could be blocked by the Wue-1 monoclonal antibody.

Antibodies, Bispecific↗
PubMed2004

PI3-K/AKT/FKHR and MAPK signaling cascades are redundantly stimulated by a variety of cytokines and contribute independently to proliferation and survival of multiple myeloma cells.

IL-6 has been reported to play a central role in growth and survival of multiple myeloma (MM) cells. However, recently we have demonstrated that in the presence of bone marrow stromal cells, survival of MM cells becomes independent of the IL-6/gp130/STAT3 pathway questioning the singular role of IL-6 in MM. Therefore, it was the aim of this study to identify additional factors and signaling pathways that might contribute to the growth and survival of MM cells. We found that in addition to IL-6 a number of bone marrow derived cytokines such as LIF, VEGF, bFGF, MIP-1alpha, SDF-1alpha, IL-1beta, SCF and IL-3 activate the MAPK pathway and induce proliferation of MM.1S and RPMI-8226 MM cells. In addition, these cytokines independently phosphorylate the forkhead family member FKHR via PI3-K/AKT and support survival of primary human MM cells. Inhibition of these pathways induces apoptosis in MM cell lines and primary MM cells. Thus, we provide evidence that in addition to IL-6 a number of different factors trigger important growth-promoting pathways to support the proliferation and survival of MM cells. Therefore, blocking such pathways, rather than blocking a single factor, might be a promising approach for the development of novel treatment strategies in MM.

Aged↗