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S Seeber

Publications and source records attributed to S Seeber.

At least 91 records · Page 5Linked to original sources
PubMed1999

Transfer of the cytidine deaminase cDNA into hematopoietic cells.

In order to investigate whether transfer of the cytidine deaminase (CDD) cDNA would increase chemotherapy resistance to cytosine arabinoside (ara-C) we used a retroviral vector expressing both, neomycin phosphotransferase and the CDD cDNA, to transduce hematopoietic cells from cell lines and from murine bone marrow (BM). After coculture on producer clones with a viral titer of 1 x 10(5) CFU/ml and up to 3-fold increased CDD enzymatic activity, WEHI-3 cell line and primary hematopoietic cells were exposed to ara-C in clonogenic assays. A transduction efficiency of 34.8 +/- 6.2% could be determined for BM clonogenic progenitor cells by G418 resistance. We could observe significantly more colonies (77 +/- 3.1%) surviving from transduced primary BM cells than from mock cells (51.7 +/- 9.3%) at 10(-8) mol/l ara-C. At 10(-7) mol/l ara-C 8.7% of BM cells became absolutely resistant after retroviral transduction. Our data confirm that CDD represents another candidate gene for increasing resistance to cytotoxic drugs in hematopoietic cells.

3T3 Cells↗
PubMed1999

Relation between S-phase fraction of myeloma cells and anemia in patients with multiple myeloma.

In an attempt to define the relation among anemia, tumor mass, and proliferative activity of tumor cells in vivo, we measured the proportion and cell cycle distribution of erythropoietic cells and myeloma cells in the bone marrow of patients with multiple myeloma using four-parameter flow cytometry. Forty-three bone marrow samples from 33 patients with stage II or III disease and normal renal function at diagnosis (n = 9), in partial remission (n = 9), and in progression or relapse after chemotherapy (n = 25) were evaluated. Early and late erythropoietic cells were discriminated based on published light scatter properties in combination with CD71 expression. Myeloma cells were detected by exploiting their strong CD38 positivity and light scatter characteristics. Cell cycle distribution of the three cell populations was determined by propidium iodine staining. In the whole group of patients, hemoglobin (Hb) concentration was inversely correlated with beta2-microglob-ulin (p = 0.03), percentage of marrow CD38++ cells (p = 0.008), and percentage of CD38(++) cells in S phase (S-CD38++; p < 0.001). Partial correlation analysis revealed S-CD38++ to be the only independent predictor of Hb concentration (p < 0.001). No correlation was found between Hb concentration and the S-phase fraction of erythropoietic cells. In the subgroup of patients with moderate to severe anemia, defined as Hb concentration <11 g/dL, Hb level correlated negatively only with S-CD38++ (p < 0.001) but not with beta2-microglobulin and percentage of marrow CD38++ cells. In addition, Hb and the S-phase proportion of early erythropoietic cells correlated positively (p = 0.029). The strong inverse correlation between Hb concentration and percentage of myeloma cells in S phase suggests that in multiple myeloma, tumor proliferative activity may have a more important impact on the development of anemia than tumor mass. The S-phase fraction of tumor cells appears to be the most important pathogenic factor, especially in anemic patients. In these patients, the positive relation between Hb concentration and the S-phase fraction of erythropoietic progenitors indicates that development of anemia is associated with inhibition of erythropoiesis.

ADP-ribosyl Cyclase↗
PubMed1999

Maintenance treatment with medroxyprogesterone acetate in patients with advanced breast cancer responding to chemotherapy: results of a randomized trial. Essen Breast Cancer Study Group.

The purpose of this randomized phase III trial was to study whether medroxyprogesterone acetate (MPA) maintenance treatment prolongs the time to progression in advanced breast cancer patients responding to an induction chemotherapy. Patients with progressive advanced breast cancer previously untreated with anthracylines and progestins were given epirubicin (30 mg/m2) and ifosfamide (2 g/m2) on days 1 and 8 at 3-weekly intervals. Patients without disease progression after 6 cycles of chemotherapy were randomly assigned to receive, until progression, either no treatment or MPA at a daily total dose of 500 mg. Ninety patients were randomized: 46 to the MPA arm and 44 to the observation arm. Median time to progression was longer in the MPA arm: 4.9 months versus 3.7 months in the intent-to-treat analysis (p = 0.02), and 4.9 months versus 3.0 months in the secondary efficacy analysis (p = 0.012). Seven patients were removed from MPA due to side effects. The changes in patient-rated quality of life scores were similar in both groups. The median length of survival from randomization was 17.4 months for patients receiving MPA and 18.3 months for patients randomized to observation (p = 0.39). In conclusion, in patients with advanced breast cancer achieving remission or non-progression with 6 cycles of epirubicin and ifosfamide chemotherapy, MPA maintenance treatment led to a significant, though modest, prolongation of the time to progression without affecting overall survival of the study patients.

Aged↗
PubMed1999

Prognostically orientated multimodality treatment including surgery for selected patients of small-cell lung cancer patients stages IB to IIIB: long-term results of a phase II trial.

Following mediastinoscopy, a prognostically orientated multimodality approach was chosen in selected small-cell lung cancer (SCLC) patients with hyperfractionated accelerated chemoradiotherapy (Hf-RTx) and definitive surgery (S). Stage IB/IIA patients had four cycles of cisplatin/etoposide (PE) and surgery. Stage IIB/IIIA patients had three cycles PE followed by one cycle concurrent chemoradiation including Hf-RTx and surgery. Most stage IIIB patients were not planned for surgery and had CTx followed by sequential RTx or one cycle concurrent CTx/RTx. Of 46 consecutive patients (stage IB six, IIA two, IIB/IIIA 22, IIIB 16) 43 (94%) showed an objective response. Twenty-three of patients (72%) planned for inclusion of S were completely resected (R0) (IB 6/6, IIA 2/2, IIB/IIIA 13/22, IIIB 2/2). Overall toxicity was acceptable--one patient died of septicaemia, no perioperative deaths occurred. Median follow-up of patients alive (n = 21) is 52 months (30+ - 75+). Median survival and 5-year survival rate of all patients are 36 months and 46%, in R0 patients 68 months and 63% (R0-IIB/IIIA/IIIB: not yet reached and 67%). This multimodality treatment including surgery proved highly effective with 100% local control and remarkable long-term survival after complete resection, even in locally advanced SCLC stages IIB/IIIA patients.

Adolescent↗
PubMed1999

Reversal of MDR1-associated resistance to topotecan by PAK-200S, a new dihydropyridine analogue, in human cancer cell lines.

Recent data suggest that expression of the membrane P170-glycoprotein (P-gp) may confer resistance to the topoisomerase-I-interactive agent topotecan. The present study describes the cellular effects of a new dihydropyridine analogue, PAK-200S, on P-gp-mediated resistance to topotecan in human breast and ovarian tumour cells. PAK-200S at a non-cytotoxic concentration of 2.0 microM completely reversed resistance to topotecan in P-gp-expressing MCF-7/adr (breast) and A2780/Dx5 (ovarian) tumour cells, respectively, with no effects on parental cells. Cellular pharmacokinetic studies by reversed-phase high-performance liquid chromatography analysis showed significantly lower cellular drug concentrations of the pharmacologically active closed-ring lactone of topotecan in multidrug-resistant cells than in parental cells. PAK-200S was effective in restoring the cellular lactone concentrations of topotecan in resistant MCF-7/adr cells to levels comparable to those obtained in parental cells. Furthermore, exposure of MCF-7/adr cells to topotecan in the presence of PAK-200S significantly increased the induction of protein-linked DNA breaks. PAK-200S did not alter nuclear topoisomerase I-mediated ex vivo pBR322 DNA plasmid unwinding activity and topoisomerase-I protein expression. These results suggest that reversal of P-gp-mediated resistance to topotecan by PAK-200S was related to the restoration of cellular drug concentrations of the active lactone form of topotecan rather than a direct effect on topoisomerase-I function.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Induction chemotherapy followed by concurrent chemotherapy and high-dose radiotherapy for locally advanced squamous cell carcinoma of the cervical oesophagus.

The efficacy and toxicity of combined radiochemotherapy for locally advanced squamous cell carcinomas of the cervical oesophagus was evaluated retrospectively. Induction chemotherapy consisted of three courses of 5-fluorouracil (5-FU), leucovorin, etoposide and cisplatin (FLEP) or two courses weekly six times of 5-FU and leucovorin combined with biweekly cisplatin. This induction regimen was followed by high-dose external beam radiotherapy up to 60-66 Gy and concurrent chemotherapy with cisplatin and etoposide. Median follow-up of the recruited 17 patients was 37 months (13-73 months). Long-term survival was 24% at 2 and 3 years. The probabilities of locoregional tumour recurrences and distant metastases as sites of first relapse were 67 and 39% at 2 years. Acute and late toxicity of this schedule was moderate. The protocol offers a definitive chance of long-term survival for patients with locally advanced carcinomas of the cervical oesophagus, but local in-field recurrences remain the predominant risk after treatment. Intensification of the regimen seems possible because no dose-limiting late toxicities were observed.

Adult↗
PubMed1999

Gemcitabine as a single agent in the treatment of relapsed or refractory aggressive non-Hodgkin's lymphoma.

PURPOSE: A multicenter phase II trial was conducted to evaluate the efficacy and toxicity of gemcitabine in patients with relapsed or refractory aggressive non-Hodgkin's lymphomas (NHL). PATIENTS AND METHODS: Thirty-one patients with B-cell intermediate or high-grade NHL (Working Formulation) were enrolled onto the study. The median age was 61 years, with a Karnofsky performance status of </= 80% in 65% of patients. Forty-eight percent had stage III or IV (Ann Arbor Classification) at study entry. Pretreatment consisted of one, two, or three chemotherapeutic regimens in nine, 11, and 11 patients, respectively. Gemcitabine 1,250 mg/m(2) was administered intravenously over 30 minutes on days 1, 8, and 15 of a 28-day schedule. RESULTS: Thirty patients were assessable for efficacy, and 31 were assessable for toxicity. No complete responses were observed, but six patients showed a partial response, 11 stable disease, and 13 progressive disease. The overall response rate was 20% (95% confidence interval, 8% to 39%) for assessable patients and 19% (95% confidence interval, 8% to 34%) for the intent-to-treat analysis. The median duration of partial response was 6 months (range, 3.7 to 15+ months). Nonhematologic World Health Organization grade 3 toxicity included hepatic toxicity in four patients and infection in two. Hematologic toxicity was observed as grade 3 anemia in three patients, grade 3 leukopenia in two patients, grade 3/4 neutropenia in two patients, and grade 3/4 thrombocytopenia in six patients. CONCLUSION: The present schedule of gemcitabine displays modest efficacy and mild toxicity in pretreated aggressive NHL.

Adult↗
PubMed1999

Phase I study of a weekly schedule of irinotecan, high-dose leucovorin, and infusional fluorouracil as first-line chemotherapy in patients with advanced colorectal cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) of a weekly schedule of irinotecan (CPT-11), leucovorin (LV), and a 24-hour infusion of fluorouracil (5-FU24h) as first-line chemotherapy in advanced colorectal cancer and to assess preliminary data on the antitumor activity. PATIENTS AND METHODS: Twenty-six patients with measurable metastatic colorectal cancer were entered onto this phase I study. In the first six dose levels, fixed doses of CPT-11 (80 mg/m2) and LV (500 mg/m2) in combination with escalated doses of 5-FU24h ranging from 1.8 to 2.6 g/m2 were administered on a weekly-times-four (dose levels 1 to 4) or weekly-times-six (dose levels 5 to 6) schedule. The dose of CPT-11 was then increased to 100 mg/m2 (dose level 7). RESULTS: Seventy-nine cycles of 5-FU24h/LV with CPT-11 were administered in an outpatient setting. No dose-limiting toxicities were observed during the first cycle at dose levels 1 to 6, but diarrhea of grade 4 (National Cancer Institute common toxicity criteria) was observed in three patients after multiple treatment cycles. Other nonhematologic and hematologic side effects, specifically alopecia and neutropenia, did not exceed grade 2. With the escalation of CPT-11 to 100 mg/m2 (dose level 7), diarrhea of grade 3 or higher was observed in four of six patients during the first cycle; thus, the MTD was achieved. Sixteen of 25 response-assessable patients (64%; 95% confidence interval, 45% to 83%) achieved an objective response. CONCLUSION: The recommended doses for further studies are CPT-11 80 mg/m2, LV 500 mg/m2, and 5-FU24h 2.6 g/m2 given on a weekly-times-six schedule followed by a 1-week rest period. The addition of CPT-11 to 5-FU24h/LV seems to improve the therapeutic efficacy in terms of tumor response with manageable toxicity.

Adolescent↗
PubMed1999

Prophylactic cranial irradiation in locally advanced non-small-cell lung cancer after multimodality treatment: long-term follow-up and investigations of late neuropsychologic effects.

PURPOSE: Relapse pattern and late toxicities in long-term survivors were analyzed after the introduction of prophylactic cranial irradiation (PCI) into a phase II trial on trimodality treatment of locally advanced (LAD) non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Seventy-five patients with stage IIIA(N2)/IIIB NSCLC were treated with induction chemotherapy, preoperative radiochemotherapy, and surgery. PCI was routinely offered during the second period of study accrual. Patients were given a total radiation dose of 30 Gy (2 Gy per daily fraction) over a 3-week period starting 1 day after the last chemotherapy cycle. RESULTS: Introduction of PCI reduced the rate of brain metastases as first site of relapse from 30% to 8% at 4 years (P =.005) and that of overall brain relapse from 54% to 13% (P <.0001). The effect of PCI was also observed in the good-prognosis subgroup of 47 patients who had a partial response or complete response to induction chemotherapy, with a reduction of brain relapse as first failure from 23% to 0% at 4 years (P =.01). Neuropsychologic testing revealed impairments in attention and visual memory in long-term survivors who received PCI as well as in those who did not receive PCI. T2-weighted magnetic resonance imaging revealed white matter abnormalities of higher grades in patients who received PCI than in those who did not. CONCLUSION: PCI at a moderate dose reduced brain metastases in LAD-NSCLC to a clinically significant extent, comparable to that in limited-disease small-cell lung cancer. Late toxicity to normal brain was acceptable. This study supports the use of PCI within intense protocols for LAD-NSCLC, particularly in patients with favorable prognostic factors.

Adult↗
PubMed1999

Paclitaxel and UFT plus oral calcium folinate in pretreated metastatic breast cancer.

This phase I study was designed to determine the maximum tolerated dose (MTD) and dose-limiting side effects of combination treatment with paclitaxel (Taxol) and UFT (uracil and tegafur in a 4:1 molar ratio) plus oral calcium folinate (Orzel) for advanced metastatic breast cancer. After premedication, patients received paclitaxel as a 3-hour IV infusion (175 mg/m2) on day 1; UFT was administered orally at 300 mg/day (dose level 1), 400 mg/day (dose level 2), 500 mg/day (dose level 3), or 600 mg/day (dose level 4) in combination with 90 mg/day of calcium folinate in three divided doses for 14 days. Twenty patients with pretreated metastatic breast cancer have entered the trial so far. The main toxicity was neutropenia, occurring in 68% of patients. World Health Organization grades 1 and 2 peripheral neuropathy, arthralgia, and myalgia were common but not dose-limiting. All patients had grade 3 alopecia due to paclitaxel. One of six patients treated at dose level 4 experienced a dose-limiting toxicity with neutropenic fever. But within four dose levels MTD was not reached, and the study will continue to accrue patients to dose level 5. Objective responses were observed at all dose levels. In conclusion, the combination of paclitaxel and UFT plus oral calcium folinate seems to be a convenient and effective regimen for patients with pretreated metastatic breast cancer. Phase I is ongoing in order to determine MTD and the recommended dose for phase II testing.

Administration, Oral↗
PubMed1998

Frequency of clonal B lymphocytes in chronic myelogenous leukemia evaluated by fluorescence in situ hybridization.

The demonstration of the Philadelphia (Ph) chromosome in B lymphocytes from patients with chronic myelogenous leukemia (CML) has provided evidence that the disorder originates in a pluripotent progenitor cell. Divergent results, however, exist as to the degree of contribution of clonally derived cells to the B-cell compartment. To address this issue, B lymphocytes were selected from the blood of seven patients in the chronic phase of Ph-positive CML and were examined with dual-color fluoresence in situ hybridization for the presence of the Ph translocation. The purity of the B-cell preparations ranged from 88% to 97% (mean 93%). The Ph translocation was detected in 22-34% (mean, 27%) of the sorted B cells. There was no evidence that the duration of the disease affects the ratio of Ph-positive and -negative B cells. In summary, clonally derived circulating B lymphocytes were present in all patients studied but made only minor contribution to this compartment.

Adult↗
PubMed1998

Clinical pharmacokinetics of intravenous treosulfan in patients with advanced solid tumors.

Treosulfan (L-threitol- 1,4-bis-methanesulfonate, Ovastat) is a prodrug of a bifunctional alkylating agent with activity in ovarian carcinoma and other solid tumors. For a clinical and pharmacology study, patients with advanced, refractory, or resistant solid tumors were treated with a single-dose intravenous 30-min infusion of 8 or 10 g/m2 treosulfan. A sensitive method for the determination of treosulfan in plasma and urine by reverse-phase high-performance liquid chromatography was developed. A total of 14 plasma and urine treosulfan pharmacokinetics determinations were analyzed in the 8-g/m2 group and 7 were analyzed in the 10-g/m2 group, the maximum tolerated dose for this group of pretreated patients. The terminal half-life of treosulfan was in the range of 1.8 h. AUC and Cmax values were significantly (P < 0.01) higher in the 10-g/m2 group (AUC 708+/-168 versus 977+/-182 microg ml(-1) h, Cmax 465+/-98 versus 597+/-94 microg/ml). The mean urinary excretion of the parent compound was about 25% of the total dose delivered over 48 h (range 5-49%), and about 20% was excreted during the first 6 h after administration. Currently, a clinical phase I pharmacokinetics and dose-escalation trial with autologous blood stem-cell support has been started at 20 g/m2 treosulfan using a 2-h infusion protocol.

Adult↗
PubMed1998

Bendamustine as salvage treatment in patients with advanced progressive breast cancer: a phase II study.

A phase II pilot study of bendamustine as salvage treatment in patients with advanced breast cancer was performed to determine the objective response rates and make further observations on the toxicity of this drug. A group of 37 patients, pretreated with chemotherapy for advanced disease, entered the trial. Treatment consisted of 150 mg/m2 bendamustine on days 1 and 2 of a 4-week treatment course. Patients continued to receive treatment until complete remission and then two further courses, until tumour progression or unacceptable toxicity ensued. A total of 36 patients received at least one treatment course and were assessable for toxicity; 33 patients were evaluable for treatment results. Dose-limiting grade 3 and 4 WHO toxicity occurred in 5 and 3 patients respectively; 27% of patients entered complete or partial tumour remission. The median time to tumour progression was 2 months with a range of 1-14 months. The efficacy of bendamustine was apparently independent of pretreatment with anthracyclines, suggesting a lack of cross-resistance between bendamustine and anthracyclines. It can be concluded that bendamustine in the dose and application schedule used here is active in the salvage therapy of women with advanced breast cancer. The toxicity was acceptable. Future studies have to confirm the data of this pilot trial and to define the role of bendamustine in the combination chemotherapy of metastatic breast cancer that has been suggested by previous trials.

Adult↗
PubMed1998

Chronic myelogenous leukemia: effect of interferon-alpha treatment on phagocytic activity and capacity of circulating neutrophils.

This study focuses on the effect of interferon (IFN)-alpha on phagocytosis of FITC-labeled Escherichia coli by polymorphonuclear neutrophils (PMNs) in chronic myelogenous leukemia (CML). The phagocytic activity and capacity of PMNs from IFN-alpha treated patients (n = 17), untreated CML patients (n = 9) and from healthy donors (n = 20) were compared using flow cytometry. Both parameters of PMN phagocytosis were reduced in untreated CML and in IFN-alpha treated CML with Ph1 chromosome persistence but normal in IFN-alpha treated CML with Ph1 conversion. Thus, the phagocytic performance of PMNs in patients with chronic phase CML is significantly improved after successful treatment with IFN-alpha.

Adolescent↗
PubMed1998

Assessment of resistance induction to cytosine arabinoside following transfer and overexpression of the deoxycytidylate deaminase gene in vitro.

Recent attempts to protect hematopoietic progenitor cells from cytarabine (ara-C)-induced toxicity by transfer of the cytidine deaminase (CDD) gene resulted in efficient in vitro inducibility of ara-C resistance. Another enzyme involved in intracellular ara-CTP inactivation is the deoxycytidylate deaminase (dCMPD). We therefore transfected the human dCMPD cDNA gene into murine fibroblasts and investigated the relationship of forced dCMPD expression and resistance induction to ara-C. Several cell lines were established which demonstrated a 1.7-3.5-fold increase in cellular dCMPD activity and an up to 2-fold increase in the IC50 value of ara-C. However, increases in dCMPD activities did not show a positive linear correlation with the induction of ara-C resistance. In addition, CD34 + hematopoietic progenitor cells revealed the highest endogenous dCMPD enzyme levels among different human hematopoietic cells. Thus, despite the documented role for dCMPD in ara-CTP inactivation of certain cell types, these results suggest that the dCMPD gene may prove less useful than the CDD gene as a therapeutic target in attempts to attenuate ara-C-induced bone marrow toxicity.

Animals↗
PubMed1998

Phase I study of a weekly 1 h infusion of paclitaxel in patients with unresectable hepatocellular carcinoma.

The majority of patients with hepatocellular carcinoma will develop either unresectable or metastatic disease and, therefore, are candidates for systemic chemotherapy. Only a few chemotherapeutic agents have shown documented activity in the treatment of advanced hepatocellular carcinoma and there is clearly a need for the evaluation of new active drugs. Therefore, we performed a phase I trial with a weekly schedule of paclitaxel in patients with advanced hepatocellular carcinoma. 16 patients with documented progression of unresectable hepatocellular carcinoma were included. After premedication, paclitaxel was given as a 1 h infusion on days 1, 8, 15, 22, 29 and 36 representing one treatment cycle. The cycle was repeated every 50 days. The starting dose was 70 mg/m2 and the doses were escalated in steps of 10 mg/m2/week. A minimum of 3 patients were treated at each dose level. All treatment was given on an out-patient basis. Dose-limiting toxicity was reached at a dose of 100 mg/m2/week with 2 of 6 patients treated at that dose level having WHO grade 4 neutropenia. Other toxic side-effects were only mild. 1 partial response and 9 cases with disease stabilisation were observed in 16 patients with initially progressive disease. We, therefore, conclude that the recommended dose for a further phase II trial in patients with hepatocellular carcinoma is 90 mg/m2/week. These data indicate that paclitaxel given at this dose and schedule might have activity in hepatocellular carcinoma and further investigation in phase II trials is warranted.

Adult↗
PubMed1998

Paclitaxel in combination with weekly 24-hour infusional 5-fluorouracil plus leucovorin in the second-line treatment of metastatic breast cancer: results of a phase II study.

PURPOSE: To evaluate the antitumor activity in terms of response rate (RR), time to progression (TTP) and survival of paclitaxel in combination with weekly 24-hour infusional 5-fluorouracil (5-FU)/leucovorin in pretreated metastatic breast cancer (MBC). PATIENTS AND METHODS: Fifty-four patients with bidimensionally measureable disease were included during phase II. Thirty-two had anthracycline resistant disease. Treatment consisted of 5-FU (24-hour i.v. infusion) 2.0 g/m2, leucovorin (two-hour i.v. infusion prior to 5-FU) 500 mg/m2, weekly for six weeks (day 1, 8, 15, 22, 29, 36) and paclitaxel (three-hour i.v. infusion) 175 mg/m2 was administered additionally on days 1 and 22, q 50 days. RESULTS: We observed complete remissions in 4% of patients (2 of 54), partial remissions in 55% (30 of 54), stable disease in 37% (20 of 54) and progressive disease in 4% (2 of 54). The overall RR was 59% (95% CI 48%-72%). The RR in 32 patients with anthracycline resistant disease was 59% (19 of 32). The median duration of response was 12 months (3-22), median TTP eight months (2-22) and median survival time 15 months (2-28). Neutropenia was common, but of CTC grade 2 or 3 in most patients. Nonhematologic toxicities mostly consisted of CTC grade 1 and 2 myalgia, diarrhea, mucositis, nausea and vomiting. CONCLUSIONS: Paclitaxel combined with weekly 24-hour infusional 5-FU/leucovorin is well tolerated in the second line treatment of MBC. High efficacy was documented even in the treatment of anthracycline resistant disease, which warrants further evaluations.

Adult↗