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Biomedical subjects

S Seeber

Publications and source records attributed to S Seeber.

At least 19 recordsLinked to original sources
PubMed2006

Differential expression of drug-resistance-related genes between sensitive and resistant blasts in acute myeloid leukemia.

Drug resistance constitutes a considerable problem in the therapy of acute myeloid leukemia (AML). In order to identify genes which might be related to drug resistance, we retrospectively studied gene expression patterns in blast populations of 14 patients with de novo AML, focusing on known or potential resistance mechanisms against cytosine arabinoside and anthracyclines. Following induction and postremission chemotherapy, 7 patients achieved a complete remission (CR) for more than 1 year, while 7 patients showed blast persistence (BP) after induction and salvage chemotherapy. Gene expression analysis was performed using RNA extracted from archived guanidine extracts and Affymetrix HGU133A gene chips. We utilized the Gene Ontology category Biological Process to select genes implicated in DNA metabolism, nucleoside and nucleotide metabolism and transport, reactive oxygen species metabolism, apoptosis and response to drugs and identified 32 differentially expressed genes. From this functional perspective, we found differences between the CR and BP groups with regard to nucleotide metabolism (PBEF1, G6PD; p = 0.048), apoptosis (TNFAIP3, TNFAIP8, MPO, BCL2A1, BAX, SON, BNIP3L; p = 0.039) and reactive oxygen species metabolism (SOD2, KIAA0179; p = 0.048). However, the attempt to construct a predictive model of chemoresistance failed. BP samples had a 2-fold higher expression of CD34 than CR samples. Thus, our findings are in line with reports describing differences in apoptosis resistance between CD34+ and CD34- blast populations. Taken together, our results suggest that drug resistance in AML is a heterogenous phenomenon that might be better defined by means of disturbed biological processes than by focusing on the alteration of the expression of distinct genes.

Acute Disease↗
PubMed2006

Evaluation of different protocols for gene transfer into non-obese diabetes/severe combined immunodeficiency disease mouse repopulating cells.

PURPOSE: Although gene transfer with retroviral vectors has shown distinct clinical success in defined settings, efficient genetic manipulation of hematopoietic progenitor cells remains a challenge. To address this issue we have evaluated different transduction protocols and retroviral constructs in the non-obese diabetes (NOD)/severe combined immunodeficiency disease (SCID) xenograft model. METHODS: An extended transduction protocol requiring 144 h of in vitro manipulation was compared to a more conventional protocol requiring 96 h only. RESULT: While pretransplantation analysis of cells transduced with a retroviral vector, expressing the enhanced green fluorescent protein (EGFP) marker gene, demonstrated significantly higher overall transduction rates for the extended protocol (33.6 +/- 2.3 vs. 22.1 +/- 3.8%), EGFP expression in CD34+ cells before transplantation (4.0 +/- 0.9 vs. 11.6 +/- 2.5%), engraftment of human cells in NOD/SCID bone marrow 4 weeks after transplantation (4.5 +/- 1.7 vs. 36.5 +/- 9.4%) and EGFP expression in these cells (0 +/- 0 vs. 11.3 +/- 2.8%) were significantly impaired. When the 96 h protocol was used in combination with the spleen focus forming virus (SFFV)/murine embryonic stem cell (MESV) hybrid vector SFbeta11-EGFP, high transduction rates for CD45+ (41.0 +/- 5.3%) and CD34+ (38.5 +/- 3.7%) cells prior to transplantation, as well as efficient human cell engraftment in NOD/SCID mice 4 weeks after transplantation (32.4 +/- 3.5%), was detected. Transgene expression was observed in B-lymphoid (15.9 +/- 2.0%), myeloid (36.5 +/- 3.5%) and CD34+ cells (10.1 +/- 1.5%). CONCLUSION: Our data show that CD34+ cells maintained in cytokines for multiple days may differentiate and loose their capacity to contribute to the haematological reconstitution of NOD/SCID mice. In addition, the SFFV/MESV hybrid vector SFbeta11-EGFP allows efficient transduction of and gene expression in haematopoietic progenitor cells.

Animals↗
PubMed2006

Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors.

BACKGROUND: Sorafenib (BAY 43-9006), a novel, oral multi-kinase inhibitor, blocks serine/threonine and receptor tyrosine kinases in the tumor and vasculature. Sorafenib demonstrated single-agent activity in Phase I studies, and was tolerated and inhibited tumor growth in combination with doxorubicin in preclinical studies. This Phase I dose-escalation study determined the safety, pharmacokinetics and efficacy of sorafenib plus doxorubicin. PATIENTS AND METHODS: Thirty-four patients with refractory, solid tumors received doxorubicin 60 mg/m(2) on Day 1 of 3-week cycles, and oral sorafenib from Day 4 of Cycle 1 at 100, 200 or 400 mg bid. RESULTS: Common drug-related adverse events were neutropenia (56%), hand-foot skin reaction (44%), stomatitis (32%), and diarrhea (32%). The maximum tolerated dose was not reached. One patient with pleural mesothelioma achieved a partial response (modified WHO criteria) and remained on therapy for 39.7 weeks. Fifteen patients (48%) achieved stable disease for >/=12 weeks. Doxorubicin exposure increased moderately with sorafenib 400 mg bid. The pharmacokinetics of sorafenib and doxorubicinol were not affected. CONCLUSION: Sorafenib 400 mg bid plus doxorubicin 60 mg/m(2) was well tolerated. The increased doxorubicin exposure with sorafenib 400 mg bid did not result in significantly increased toxicity; low patient numbers make the clinical significance of this unclear. These promising efficacy results justify further clinical investigation.

Adult↗
PubMed2006

Pooled safety analysis of BAY 43-9006 (sorafenib) monotherapy in patients with advanced solid tumours: Is rash associated with treatment outcome?

In this analysis of the safety and efficacy of BAY 43-9006 (sorafenib) -- a novel, oral multi-kinase inhibitor with effects on tumour and its vasculature -- pooled data were obtained from four phase I dose-escalation trials. Time to progression (TTP) was compared in patients with/without grade 2 skin toxicity/diarrhoea. Grade 3 hand-foot skin reactions (HFS; 8%) and diarrhoea (6%) were common. At the recommended 400mg bid dose for phase II/III trials (RDP), 15% of patients experienced grade 2/3 HFS, and 24% experienced grade 2/3 diarrhoea. Sorafenib induced stable disease for 6 months in 12% of patients (6% stabilized for 1 year). Patients receiving sorafenib doses at or close to the RDP, who experienced skin toxicity/diarrhoea, had a significantly increased TTP compared with patients without such toxicity (P < 0.05). Sorafenib was well tolerated at the RDP, and induced sustained disease stabilization, particularly in patients with skin toxicity/diarrhoea.

Administration, Oral↗
PubMed2006

[Metastases with CUP syndrome].

Carcinoma of unknown primary is common, accounting for 2-6% of all cancer patients. The primary site is found in less than 25% of patients before death and frequently goes undiscovered at postmortem examination. At the time point of first diagnosis of CUP syndrome, usually more than 80% of the patients present a disseminated situation. Prognosis depends on the involved site and is unaffected by whether or not the primary site is ever found. For patients presenting with metastasis to peripheral lymph nodes, node dissection may be curative. In patients with small cell malignancies, peritoneal carcinomatosis (in women), poorly differentiated carcinomas involving external lymph nodes, mediastinum, or retroperitoneum, but without metastases to viscera or bone, objective long-term responses are possible with combination chemotherapy. For all other patients, toxic therapies are recommended only for patients with good functional status, for palliation of symptoms when they develop, and for continuous support of the quality of life.

Antineoplastic Agents↗
PubMed2005

Risk factors for venous thromboembolic events in cancer patients.

BACKGROUND: Cancer patients of the Department of Internal Medicine (Cancer Research) of the Essen University Medical School (Tumor Clinics), Germany, were examined and questioned with the aim of identifying those who run a high risk of deep vein thrombosis (DVT). PATIENTS AND METHODS: Between September 2002 and April 2003, cancer therapy and DVT risk factors of 507 cancer patients (53% males, 47% females, mean age 56+/-12 years) were documented. During a mean follow-up of 8+/-5 months, 60 patients (12%) suffered from new venous thromboembolic events (VTE): 28 at the lower limb, 25 at the upper limb and 13 pulmonary embolisms. RESULTS: The following factors were considered as predictive for an increased VTE risk: inpatient treatment (P<0.0001), prior DVT in medical history (P=0.0275), DVT in family (P=0.0598), chemotherapy (P=0.0080), fever (P=0.0093) and CRP (P<0.001). After combining factors in one variable (number of factors) the predicted VTE risk increased with the number of factors in both outpatients (OR 1.85, 95% CI 1.18-2.88, P=0.0071) and inpatients (OR 2.34, 95% CI 1.63-3.36, P<or=0.0001). In the absence of all these factors the predicted VTE risk was 2.3%, increasing to 72% if all were present. CONCLUSIONS: In cancer patients the risk of VTE steadily increases with the number of risk factors, and identification of patients at high risk is possible.

Anticoagulants↗
PubMed2005

Validation of protein kinase CK2 as oncological target.

Protein kinase CK2 is a highly conserved enzyme composed of two catalytic subunits alpha and/or alpha' and two regulatory subunits beta whose activity is elevated in diverse tumour types as well as in highly proliferating tissues. Several results suggest that the overexpression of either CK2 catalytic subunits or the CK2 holoenzyme contributes to cellular transformation. In a similar vein, experiments performed compromising the intracellular expression of CK2 has led to somehow contradictory results with respect to the ability of this enzyme to control survival and apoptosis. To better elucidate the role of CK2 in programmed cell death, we have depleted cells of CK2 catalytic subunits by the application of antisense oligodeoxynucleotides and siRNAs techniques, respectively. Our results indicate that protein kinase CK2 is characterized by an extremely high stability that might be due to its association with other intracellular proteins, enhanced half-life or lower vulnerability towards proteolytic degradation. In addition, we show that despite the effectiveness of the methods applied in lowering CK2 kinase activity in all cells investigated, CK2 might not by itself be sufficient to trigger enhanced drug-induced apoptosis in cells.

Apoptosis↗
PubMed2005

Resistance to cytarabine and gemcitabine and in vitro selection of transduced cells after retroviral expression of cytidine deaminase in human hematopoietic progenitor cells.

Overexpression of the detoxifying enzyme cytidine deaminase (CDD) renders normal and leukemic hematopoietic cells resistant to cytarabine (1-beta-D-arabinofuranosylcytosine), and studies on murine cells have suggested transgenic CDD overexpression as a way to reduce the substantial myelotoxicity induced by the deoxycytidine analogs cytarabine and gemcitabine (2',2'-difluorodeoxycytidine). We now have investigated CDD (over-)expression in the human hematopoietic system. Retroviral gene transfer significantly increased the resistance of CDD-transduced cord blood and peripheral blood-derived progenitor cells for doses ranging from 20-100 nM cytarabine and 8-10 nM gemcitabine. Protection was observed for progenitors of erythroid as well as myeloid differentiation, though the degree of protection varied for individual drugs. In addition, significant selection of CDD-transduced cells was obtained after a 4-day culture in 30-100 nM cytarabine. Thus, our data demonstrate that overexpression of CDD cDNA results in significant protection of human progenitors from cytarabine- as well as gemcitabine-induced toxicity, and allows in vitro selection of transduced cells. This strongly argues for a potential therapeutic role of CDD gene transfer in conjunction with dose-intensive cytarabine- or gemcitabine-containing chemotherapy regimen.

Cells, Cultured↗
PubMed2005

[Surveillance in women with early breast cancer, systematic versus symptom guided follow-up].

Nearly all national (AGO, DKG) and international guide lines (e. g. ASCO) for follow-up of breast cancer patients do not explicitly recommend regular laboratory and radiological/ultrasound screening procedures. According to these guide lines, follow-up should be focused on the breast, only patients with possibly tumour related symptoms should be screened for metastatic disease. The rejection of more time-consuming and costlier follow-up examinations remains a contradiction to established follow-up guide lines for other solid tumours. In addition, treatment options for metastatic breast cancer disease have improved continuously over the last years. However, treatment options are considerably limited in advanced disease, if e. g. symptoms like dyspnoea or jaundice are already present at first diagnosis of metastatic disease. Therefore we will review available data of older studies as well as discuss arguments for a systematic surveillance in high-risk breast cancer patients. Overall, symptom guided follow-up seems to be adequate for patients with small primary tumours, no lymph node involvement and therefore a high curative probability, whereas in the authors' opinion systematic surveillance should be recommended for high risk patients even in the absence of symptoms. All patients, however, should be fully informed about the possibility of metastatic disease development and should be enabled to select the quality of their postoperative follow-up.

Breast Neoplasms↗
PubMed2005

Phase I/II study of capecitabine and vinorelbine in pretreated patients with metastatic breast cancer.

PURPOSE: To define the maximum-tolerated dose (MTD) and to evaluate the dose-limiting toxicities (DLT) of the combination of capecitabine and vinorelbine in patients with metastatic breast cancer who relapse after adjuvant and/or first-line treatment. In addition, we aimed to obtain data on efficacy and safety at the recommended dose. PATIENTS AND METHODS: Patients with measurable metastatic breast cancer after failure of prior chemotherapy (including anthracyclines and/or taxanes) were eligible. Capecitabine was administered with a fixed dose of 1000 mg/m(2) orally twice daily for 2 weeks followed by 1 week rest. One treatment cycle consisted of 6 weeks of treatment containing two treatment periods of capecitabine. Vinorelbine was given intravenously at escalated doses of 25 mg/m(2) (dose level 1) and 30 mg/m(2) (dose level 2) on days 1 and 8, and 22 and 29. RESULTS: Thirty-three patients received a total of 91 cycles of capecitabine and vinorelbine. The median number of administered cycles per patient was three (range one to six). Thirty-one patients were evaluable for toxicity. At dose level 2 four out of seven patients experienced DLTs (nausea/vomiting, febrile neutropenia, grade 4 neutropenia, infection and diarrhea); thus, the MTD was defined. In order to confirm the safety and efficacy, dose level 1 was extended to 24 patients. Two patients [8.3%; 95% confidence interval (CI) 1% to 27%] showed DLTs (hospitalization due to febrile neutropenia and prolonged neutropenia). The main toxicity was neutropenia, which was observed at National Cancer Institute Common Toxicity Criteria grade 3 and 4 in 39% of patients. The overall response rate for capecitabine and vinorelbine was 55% (95% CI 36% to 72.7%), including three patients with a complete remission. The median time to disease progression was 8 months (95% CI 4.3-11.7) with an overall survival of 19.2 months (95% CI 11.3-27.1) based on intention-to-treat analysis. CONCLUSIONS: The combination of capecitabine and vinorelbine can be administered with manageable toxicity and showed significant efficacy for patients with metastatic breast cancer even after failure of a anthracycline- and/or taxane-based therapy.

Administration, Oral↗
PubMed2005

Thalidomide in combination with vincristine, epirubicin and dexamethasone (VED) for previously untreated patients with multiple myeloma.

The present study aimed to evaluate the side-effects and efficacy of thalidomide in combination with an anthracycline-containing chemotherapy regimen in previously untreated myeloma patients. Thalidomide (400 mg/d) was combined with bolus injections of vincristine and epirubicin and oral dexamethasone (VED). Chemotherapy cycles were repeated every 3 wk until no further reduction in myeloma protein was observed, whereas the treatment with thalidomide was continued until disease progression. Thirty-one patients were enrolled, 12 patients were exclusively treated with thalidomide in combination with VED and 19 patients additionally received high-dose melphalan, for consolidation. Adverse events and response to therapy were assessed prior to treatment with high-dose chemotherapy. Response to thalidomide combined with VED was complete remission in six patients (19%), partial remission in 19 patients (61%), stable disease in five patients (16%), and progressive disease in one patient (3.2%). Grade 3 and 4 adverse events consisted of leukocytopenia in 10 patients (32%), and thrombocytopenia and anemia in one patient each (3.2%). Neutropenic infections grade 3 and 4 occurred in seven (23%) and three patients (9.7%), respectively, including two patients (6.5%) who died from septic shock. Deep vein thrombosis occurred in eight patients (26%), constipation in 20 patients (65%), and polyneuropathy in 20 patients (65%). The probability of event-free survival and overall survival in the whole group of patients at 36 months were 26 and 62%, respectively. In conclusion, the combination of thalidomide with VED appears to be highly effective in previously untreated patients with multiple myeloma, but it is associated with a high rate of thrombotic events, polyneuropathy, and neutropenic infections.

Adult↗
PubMed2004

Comparison of lenograstim and filgrastim: effects on blood cell recovery after high-dose chemotherapy and autologous peripheral blood stem cell transplantation.

PURPOSE: The aim of the study was to evaluate whether glycosylated granulocyte colony-stimulating factor (G-CSF) (lenograstim) offers a benefit over non-glycosylated G-CSF (filgrastim) in clinically relevant end points after high-dose chemotherapy (HDC) and autologous peripheral blood stem cell transplantation (PBSCT). METHODS: We retrospectively analyzed the outcome of 261 patients treated with either lenograstim (n=68) or filgrastim (n=193). Time to blood cell recovery, toxicities, and infectious complications were analyzed in a total of 469 G-CSF treatment cycles. RESULTS: Mean time to leukocyte recovery was 10.7 days (SD+/-0.9) (lenograstim) and 10.8 days (SD+/-0.6) (filgrastim), respectively. Likewise, time to thrombocyte engraftment, febrile days, duration of therapeutic antibiotic treatment, severity of non-hematological toxicities, duration of in-hospital stay, and duration of G-CSF treatment were similar in both groups. Owing to the physicochemical and pharmacokinetic properties of lenograstim, the required dose until leukocyte recovery was significantly smaller as compared to filgrastim (38.5 vs 54.0 microg/kg of body weight). CONCLUSIONS: Collectively, our data indicate that both G-CSF preparations are equally effective in hastening leukocyte recovery in the setting of high-dose chemotherapy followed by autologous PBSCT.

Adjuvants, Immunologic↗
PubMed2004

DNA sequence variations of the entire anti-Mullerian hormone (AMH) gene promoter and AMH protein expression in patients with the Mayer-Rokitanski-Kuster-Hauser syndrome.

BACKGROUND: The etiology of the Mayer-Rokitanski-Kuster-Hauser (MRKH) syndrome, where congenitally the Mullerian ducts fail to develop into the uterus, cervix and upper vagina, along with other malformations, is unresolved. Anti-Mullerian hormone (AMH) signal transduction inducing the degradation of Mullerian ducts in males is implicated in the MRKH syndrome. This study examined if DNA sequence variations are responsible for the activation of AMH and aberrant hormone levels in MRKH patients. METHODS: The entire AMH promoter and 3' regulatory elements of the constitutively expressed splicing factor SF3a2 were sequenced in 30 MRKH patients and genotyped in 48 control individuals using matrix-assisted laser desorption/ionization-time-of-flight mass spectronomy. Ovarian AMH promoter function was correlated with protein expression in plasma and peritoneal fluid of MRKH patients. RESULTS: Of six identified AMH promoter variations, two at positions -639 (SP1-binding site) and -210 [steroidogenic factor (SF)1-binding site] were homozygote in 73% of patients, and 69% of control individuals, destroying the SP1-binding site. AMH protein levels in plasma and peritoneal fluid from patients were equivalent to control individuals, however in three patients plasma levels were abnormally high. CONCLUSIONS: AMH is an important indicator for ovarian function. AMH promoter sequence variations or the previously proposed SF3a2-AMH fusion co-transcripts cannot be responsible for aberrant AMH expression leading to Mullerian duct degradation.

Abnormalities, Multiple↗
PubMed2004

Hemolytic uremic syndrome following prolonged gemcitabine therapy: report of four cases from a single institution.

Hemolytic uremic syndrome (HUS) has been described following the administration of multiple antineoplastic agents, most notably mitomycin C. More recently, several cases of gemcitabine-induced HUS have been observed with the overall incidence of gemcitabine-induced HUS estimated at 0.015-0.25%. We here report on four patients who developed HUS following gemcitabine therapy at our institution within the last year (incidence 1.4%). All these patients had advanced-stage disease, were heavily pretreated, and received prolonged gemcitabine application, suggesting that in this subgroup of patients HUS may be more frequently encountered than documented so far.

Adenocarcinoma↗