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S Seeber

Publications and source records attributed to S Seeber.

At least 127 records · Page 7Linked to original sources
PubMed1997

Rapamycin antagonizes interleukin-6 mediated growth arrest and differentiation of myeloblastic M1 cells.

The immunosuppressant rapamycin is known to be a potent inhibitor of cytokine driven proliferation of T-lymphocytes and other cell types. Here we have examined the effect of rapamycin on the myeloblastic cell line M1 which responds to interleukin-6 (IL-6) with growth arrest and monocytoid differentiation. Single-agent rapamycin led to a retardation of M cell growth. In spite of this intrinsic antiproliferative effect, rapamycin was found to abrogate IL-6 induced growth arrest. Concomitant exposure to rapamycin and IL-6 also reduced the extent of monocytoid differentiation as compared to treatment with IL-6 alone. Excess levels of the FK-506 analogue ascomycin reversed the antagonistic effect of rapamycin on IL-6 mediated growth suppression, suggesting that this biological action of rapamycin is mediated by a rapamycin/immunophilin complex. The findings demonstrate that rapamycin can also act as an antagonist of cytokine induced growth arrest and differentiation.

Animals↗
PubMed1997

Simulation of 3D-treatment plans in head and neck tumors aided by matching of digitally reconstructed radiographs (DRR) and on-line distortion corrected simulator images.

BACKGROUND AND PURPOSE: Simulation of 3D-treatment plans for head and neck malignancy is difficult due to complex anatomy. Therefore, CT-simulation and stereotactic techniques are becoming more common in the treatment preparation, overcoming the need for simulation. However, if simulation is still performed, it is an important step in the treatment preparation/execution chain, since simulation errors, if not detected immediately, can compromise the success of treatment. A recently developed PC-based system for on-line image matching and comparison of digitally reconstructed radiographs (DRR) and distortion corrected simulator monitor images that enables instant correction of field placement errors during the simulation process was evaluated. The range of field placement errors with non-computer aided simulation is reported. MATERIALS AND METHODS: For 14 patients either a primary 3D-treatment plan or a 3D-boost plan after initial treatment with opposing laterals for head and neck malignancy with a coplanar or non-coplanar two- or three-field technique was simulated. After determining the robustness of the matching process and the accuracy of field placement error detection with phantom measurements, DRRs were generated from the treatment planning CT-dataset of each patient and were interactively matched with on-line simulator images that had undergone correction for geometrical distortion, using a landmark algorithm. Translational field placement errors in all three planes as well as in-plane rotational errors were studied and were corrected immediately. RESULTS: The interactive matching process is very robust with a tolerance of <2 mm when suitable anatomical landmarks are chosen. The accuracy for detection of translational errors in phantom measurements was <1 mm and for in-plane rotational errors the accuracy had a maximum of only 1.5 degrees. For patient simulation, the mean absolute distance of the planned versus simulated isocenter was 6.4 +/- 3.9 mm. The in-plane rotational error in both planes was <3 degrees with one exception. Three large field placement errors (two patients with 11.5 and 16.0 mm distances of the planned versus simulated isocenter, respectively and one patient with a 7 degree rotational error) were detected and, as with the smaller errors, were immediately corrected. CONCLUSION: On-line image matching of treatment planning CT-derived DRRs and distortion corrected treatment simulator images is a precise and reliable method to reduce field placement errors in the simulation of complex 3D-treatment plans for head and neck malignancy and thus enhances accuracy in the first step of the treatment preparation/execution chain. However, out-of-plane rotational errors could not be assessed and assumedly they are comparatively small since due to rigid fixation, detected in-plane errors were small.

Computer Simulation↗
PubMed1997

Comparative antitumor efficacy of docetaxel and paclitaxel in nude mice bearing human tumor xenografts that overexpress the multidrug resistance protein (MRP)

BACKGROUND: Multidrug resistance has been associated with expression of the multidrug resistance protein (MRP). Recently, MRP-expression has been detected in human tumor samples of patients with breast cancer and non-small-cell lung cancer. Since taxoids are the most active drugs in the treatment of both tumor entities, the antitumor efficacies of paclitaxel and docetaxel were compared in nude mice bearing human tumor xenografts that express MRP. MATERIALS AND METHODS: Athymic nude mice (nu/nu) bearing tumor xenografts of parental human sarcoma HT1080 or MRP-expressing HT1080/DR4 cells (as confirmed by Northern blot analysis) were treated with the maximum tolerated doses (MTD) of doxorubicin ([Dx] 10 mg/kg i.v. push), paclitaxel ([PC] 50 mg/kg three-hour i.v. infusion), or docetaxel ([DC] 40 mg/kg three-hour i.v. infusion). In vitro, the activity of doxorubicin, paclitaxel and docetaxel was evaluated by the sulphorhodamine B (SRB) assay using the pyridine analogue PAK-104P (5 microM), a potent inhibitor of MRP-function. RESULTS: At their MTDs both taxoids showed significant activity against MRP-negative HT1080 xenografts with response rates of 80% (40% CR) for PC and 100% (60% CR) for DC. In contrast, DC was significantly more active than PC in nude mice bearing doxorubicin resistant MRP-expressing HT1080/DR4 tumor xenografts (overall response rates: 100% (60% CR) for DC; 10% (0% CR) for PC; 0% for Dx). Since treatment of mice with the MTD of PC or DC yielded similar overall toxicity (maximum weight loss for HT1080: PC 8.6 +/- 2.2%; DC 7.5 +/- 2.2% and for HT1080/DR4: PC 11.6 +/- 3.0%; DC 7.6 +/- 1.8%, respectively), these results demonstrate the increase in the therapeutic index for docetaxel against MRP-expressing tumors. In vitro, HT1080/DR4 cells were 270-fold, 6.4-fold and 2.8-fold more resistant than parental cells to doxorubicin, PC and DC, respectively. Pyridine analogue PAK-104P completely restored drug sensitivity to PC and DC, while no effect of PAK-104P on parental HT1080 cells was observed. CONCLUSIONS: Both taxoids, when given at their MTDs, showed significant efficacy against parental HT1080 tumor xenografts. However, docetaxel at its MTD was significantly more active against MRP-expressing tumor xenografts than paclitaxel. Furthermore, in vitro resistance of HT1080/DR4 cells was higher for PC (6.4-fold) than for DC (2.8-fold). Since PAK-104P completely restored sensitivity to both taxoids, the observed resistance appears to be related to MRP. These data suggest, that docetaxel is not as readily transported by MRP as paclitaxel leading to an increased therapeutic ratio in MRP-expressing tumors in vivo. Therefore, docetaxel may have therapeutic advantages in the clinical treatment of MRP-expressing tumors.

ATP-Binding Cassette Transporters↗
PubMed1997

Modulation of 5-fluorouracil with methotrexate and low-dose N-(phosphonacetyl)-L-aspartate (PALA) is inactive in advanced pancreatic carcinoma.

PURPOSE: To evaluate the effect of biochemical modulation by PALA and methotrexate on the therapeutic activity of 5-fluorouracil (5-FU) in patients with advanced pancreatic adenocarcinoma. PATIENTS AND METHODS: The treatment protocol consisted of phosphonacetyl-L-aspartate (PALA) 250 mg/m2 i.v. 15-minute infusion followed by methotrexate 200 mg/m2 i.v. 30-minute infusion on day 1 and 5-FU 600 mg/m2 i.v. push on day 2. Folinic acid was given at 15 mg/m2 p.o. every six hours for eight doses, starting 24 hours after methotrexate infusion. Cycles were repeated every two weeks. RESULTS: Thirty patients with advanced chemotherapynaive pancreatic cancer were included; 26 had measurable disease. Median age 56 years (27-72); median PS 1 (0-2). One PR (3.9%) was achieved; nine patients had stable disease. Median time to progression was 91 days. Median survival was 177 days and one year survival was 13.3% (4 of 30 patients). Treatment was well tolerated; diarrhea WHO grade 2 or 3 occurred in six patients; stomatitis WHO grade 2 and 3 in nine patients. CONCLUSIONS: Modulation of 5-FU by PALA and MTX given in this dose and schedule appears to be ineffective in patients with advanced pancreatic adenocarcinoma.

Adenocarcinoma↗
PubMed1997

Phase II trial of continuous oral trofosfamide in patients with advanced colorectal cancer refractory to 5-fluorouracil.

Fourteen patients with 5-fluorouracil (5-FU) refractory, progressive colorectal cancer metastatic to liver and/or lung were treated with continuous oral trofosfamide, an alkylating agent structurally related to cyclophosphamide and ifosfamide. Trofosfamide was given daily at 200 mg/day. No objective partial or complete responses were seen in 14 evaluable patients. There were four patients with stable disease or minor responses; the median duration of stable disease during trofosfamide treatment was 14 weeks, with of range of 12-36 weeks. Mild to moderate side effects were reported in seven patients including grade 1-2 nausea in four patients, grade 1 leukopenia in two patients and grade 1 anemia in one patient. Trofosfamide in this dose and schedule shows minor activity in 5-FU refractory colorectal cancer. Because of very little side effects, dose escalations appear to be possible.

Adult↗
PubMed1997

Drug interactions of 5-fluorouracil with either cisplatin or lobaplatin--a new, clinically active platinum analog in established human cancer cell lines.

Lobaplatin [1,2-diaminomethylcyclobutane platinum(II)-lactate] is a new platinum compound which appears to possess incomplete cross-resistance to cisplatin and might have a favorable pattern of side effects. Since lobaplatin has activity in esophageal cancer, combination protocols with 5-fluorouracil (5-FU) are evaluated. In order to assess the mode of action of lobaplatin when combined with 5-FU, two human cancer cell lines were treated with various combinations of 5-FU given for either 2 or 24h and lobaplatin. Drug interactions were evaluated by isobologram analysis. Lobaplatin showed basically the same interaction pattern when combined with 5-FU as cisplatin. The combination of either platinum analog with a 24 h exposure to 5-FU was superior to a short-term 5-FU exposure. Furthermore, when 5-FU was given for 24 h, no additional effect of folinic acid was seen. From these data we conclude that cisplatin and lobaplatin show similar interactions with 5-FU. Protracted infusion schedules of 5-FU appear to be more active than bolus application.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Recombinant human erythropoietin in the treatment of cancer-related anaemia.

The efficacy and safety of recombinant human erythropoietin (rhEPO) were tested when given subcutaneously (s.c.) in an escalating dose of 2000-10,000 units (U) daily in 60 patients with cancer-related anaemia (CRA). A positive response, defined as an increase in haemoglobin more than 2 g/dl and independence of blood transfusions was observed in 23 of 48 evaluable patients (48%) within a median of 8 wk. In detail, rhEPO corrected anaemia in 11 of 14 patients (79%) with malignant lymphoma, in 8 of 15 patients (53%) with multiple myeloma and in 4 of 10 patients (40%) with a solid tumour. The median dose of rhEPO in successful cases was 5000 U daily. Four patients with agnogenic myeloid metaplasia and 5 with myelodysplastic disorder failed to respond to rhEPO. No patient had any severe side effects. Pretreatment serum erythropoietin levels appeared to be a weak predictor for response to rhEPO treatment. In conclusion, rhEPO seems to be safe and effective in correcting CRA in certain groups of patients.

Adolescent↗
PubMed1997

Thymidylate synthase inhibitors in cancer therapy: direct and indirect inhibitors.

PURPOSE AND METHODS: Although fluoropyrimidines, in particular, fluorouracil (5-FU) and fluorodeoxyuridine (FdUrd), are active alone and in combination with other agents in a variety of human malignancies, therapeutic selectivity, resistance, and efficacy have been a major limitation in cancer therapy. Preclinical and clinical results in advanced and adjuvant colorectal cancers confirmed that the therapeutic efficacy of fluoropyrimidines, with thymidylate synthase (TS) as a primary target, can be improved significantly with leucovorin (LV) modulation. With the recognition that TS is an important therapeutic target, direct and specific inhibitors have been developed and are under intensive preclinical and clinical evaluation, primarily in patients with colorectal cancer, with demonstrable activity. The direct TS inhibitors have been shown to be potent, with a high level of specificity under therapeutic conditions for TS. This includes ZD1694, AG337, and LY231514. To date, although the therapeutic activity of both direct and indirect inhibitors of TS is similar, differences in the magnitude and profile of toxicity have been observed. A phase III comparative evaluation of a direct inhibitor of TS (ZD1694) with an indirect inhibitor (5-FU/LV) has been completed and showed similar activity but reduced toxicity in favor of ZD1694. RESULTS: Recognition that greater than 95% of the injected dose of 5-FU is rapidly inactivated by dihydropyrimidine dehydrogenase (DPD) to therapeutically inactive products, but with toxicity to normal tissues, led to the development of inhibitors of this enzyme with the aim to modify the therapeutic index of 5-FU. Several inhibitors in combination with 5-FU are under preclinical and clinical evaluation, including uracil and 5-chloro-2,4-dihydroxy pyridine, as modulators of 5-FU derived from its prodrug tegafur and 5-ethynyluracil as a modulator of 5-FU. CONCLUSION: In this review, an update of the present status of direct and indirect inhibitors of TS is discussed, as well as the future prospect for new drugs alone and in combination.

Antimetabolites, Antineoplastic↗
PubMed1997

Recurrence of Hodgkin's disease after 10 or more years: late relapse or de-novo malignancy due to HLA-DPB1*0301-linked susceptibility?

Recurrences of Hodgkin's disease (HD) ten or more years after initial therapy are rare and heterogeneous concerning pathological, biological and clinical features. Though usually regarded as relapses of initial disease at least part of these late recurrences may represent de-novo HD due to an increased constitutional risk. Following recent reports genetic risk for HD may be linked to the HLA-DPB1*0301 allele. Therefore, we investigated DPB1 and other HLA class I and II gene loci in three patients with very late recurrences of HD presenting at our institution within the last two years. All patients carry the HD susceptibility allele HLA-DPB1*0301. The expected probability of three patients with HD displaying the HLA-DPB1*0301 phenotype by chance is only p = 0.022. As serologic investigations also revealed Epstein-Barr virus (EBV) activity in all three cases our results support a role of genetic susceptibility possibly leading to impaired immune responses to EBV in very late recurring HD. Additionally, HLA-DPB1*0301 may be valuable for identifying patients with HD who might be candidates for a long term follow-up.

Adolescent↗
PubMed1997

Infusional 5-FU, folinic acid, paclitaxel, and cisplatin for metastatic breast cancer.

Our phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose, 24-hour infusional 5-fluorouracil(5-FU)/folinic acid (HD5-FU/FA) in intensively pretreated patients with metastatic breast cancer prompted addition of paclitaxel (Taxol) to the regimen, for a phase I/II study of outpatient second-line treatment of metastatic breast cancer. That study further prompted the addition of cisplatin (Platinol) to the regimen for first-line treatment. So far, 28 patients with metastatic breast cancer have been evaluated. Pretreatment comprised adjuvant chemotherapy in 24 of 28 patients, but no prior chemotherapy for metastatic disease. Patients were treated with HD5-FU 2 g/m2 (24-hour infusion) plus FA 500 mg/m2 (2-hour infusion prior to FU) weekly for 6 weeks (days 1, 8, 15, 22, 29, and 36); in addition, paclitaxel 175 mg/m2 (3-hour infusion) was administered on days 0 and 21 and cisplatin 50 mg/m2 (1-hour infusion) on days 1 and 22 prior to HD5-FU/FA, repeated every 50 days. Patients were treated as outpatients using Port-a-Cath systems and portable pumps. Neutropenia was common (67% World Health Organization grade 3) but mild to moderate in most patients and was of short duration. No hospitalizations were required because of febrile neutropenia, and no granulocyte colony-stimulating factor support was used. Aside from common total alopecia, nonhematologic toxicities consisted mainly of moderate myalgia, diarrhea, mucositis, and nausea and vomiting. Hand-foot syndrome and peripheral neuropathy were cumulative and occurred most commonly during the third treatment cycle, with mild-to-moderate expression. In 28 patients with bidimensionally measurable disease, 25% (7/28) attained a complete response, 57% (16/28) achieved partial response, 11% (3/28) had stable disease, and 7% (2/28) had disease progression. Overall response was 82% (95% confidence interval, 66% to 100%). Eight of 28 patients are still receiving treatment. It is concluded that the combination of paclitaxel/cisplatin with weekly HD5-FU/FA appears to be effective in the first-line treatment of metastatic breast cancer. Preliminary results must be confirmed by the final analysis of response duration, time to progression, and survival.

Adult↗
PubMed1997

A phase II trial of gemcitabine and ifosfamide in non-small cell lung cancer.

The novel nucleoside agent gemcitabine has demonstrated antitumor activity against a variety of solid tumors and is associated with low toxicity. A phase I trial in Germany of gemcitabine combined with the alkylating agent ifosfamide has shown encouraging activity against non-small cell lung cancer (NSCLC). The efficacy and toxicity of this combination was further evaluated in a phase II trial of chemotherapy-naive patients with NSCLC (mostly stage IV disease). Gemcitabine was administered at a dose of 1,000 mg/m2 on days 1, 8, and 15 followed by a 1-week rest, while ifosfamide was given at a dose of 1,500 mg/m2 on day 8 and days 9 through 12. Fifty-one of 56 patients were evaluable for response. Eleven partial responses were seen, for an overall objective response rate of 22%. The 6- and 9-month survival rates are 62% and 41%, respectively. Grade 3 and 4 neutropenia occurred in 35.8% and 24.5% of patients, respectively, but the incidence of infection was low. These results indicate that the combination of gemcitabine and ifosfamide is active against NSCLC and has a mild toxicity profile, and suggest that further evaluation of this combination is warranted.

Adult↗
PubMed1997

Metastatic breast cancer: treatment with fluorouracil-based combinations.

During the 1990s, one in nine women in the western world will be diagnosed with breast cancer, and more than 58,000 will die of the disease each year in Europe alone. Recent changes in the primary therapy of operable breast cancer have not altered patient prognosis. Adjuvant therapy delays systemic recurrence and improves survival for only a fairly selected fraction of these patients. Therapy for metastatic breast cancer has not improved significantly in recent years. While combination chemotherapy may prolong survival in selected patients, few if any achieve cure. Standard chemotherapy regimens used to treat metastatic breast cancer, such as CMF (cyclophosphamide/methotrexate/fluorouracil), FAC (5-FU/Adriamycin/cyclophosphamide), and FEC (5-FU/epirubicin/cyclophosphamide), were developed over a decade ago. Current efforts to improve therapeutic efficacy have concentrated on decreasing drug toxicity and increasing drug doses (e.g., high-dose chemotherapy with peripheral stem cell support). An important alternative to increasing therapeutic efficacy by such approaches is altering the administration schedules of well-known chemotherapeutic agents and introducing active new cytotoxic agents. One of the most frequently used cytotoxic drugs, 5-FU has documented activity in a variety of malignancies, most notably in breast cancer and gastrointestinal tract cancers. However, despite broad clinical experience, our knowledge of mechanisms of resistance in relation to various 5-FU schedules is limited. In vitro data and clinical experience show that resistance to one schedule of 5-FU can be overcome by using an alternative schedule, most often a protracted infusion.

Adult↗
PubMed1997

Infusional 5-fluorouracil/leucovorin plus paclitaxel and cisplatin in the first-line treatment of metastatic breast cancer: results of a phase II study.

Our phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose, 24-hour infusional 5-fluorouracil (5-FU)/leucovorin (LV) in intensively pretreated patients with metastatic breast cancer prompted the addition of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to the regimen for a phase I/II study of outpatient second-line treatment of metastatic breast cancer. That study further prompted the addition of cisplatin to the regimen for first-line treatment. Twenty-eight patients with metastatic breast cancer have been evaluated. Pretreatment comprised adjuvant chemotherapy in 24 of 28 patients, but no prior chemotherapy for metastatic disease. Patients were treated with high-dose 5-FU 2 g/m2 (24-hour infusion) plus LV 500 mg/m2 (2-hour infusion before 5-FU) weekly for 6 weeks (days 1, 8, 15, 22, 29, and 36); in addition, paclitaxel 175 mg/m2 (3-hour infusion) was administered on days 0 and 21 and cisplatin 50 mg/m2 (1-hour infusion) on days 1 and 22 before high-dose 5-FU/LV, repeated every 50 days. Patients were treated as outpatients using Port-a-Cath systems (SIMS Deltec Inc, St Paul, MN) and portable pumps. Neutropenia was common but mild to moderate and of short duration in most patients. No hospitalizations were required because of febrile neutropenia, and no granulocyte colony-stimulating factor support was used. Aside from common total alopecia, nonhematologic toxicities consisted mainly of moderate myalgia, diarrhea, mucositis, and nausea and vomiting. Hand-foot syndrome and peripheral neuropathy were cumulative and occurred most commonly during the third treatment cycle with mild to moderate expression. In 28 patients with bidimensionally measurable disease, 25% (seven of 28) attained a complete response, 57% (16 of 28) achieved a partial response, 11% (three of 28) had stable disease, and 7% (two of 28) had disease progression. Overall response was 82% (95% confidence interval, 66% to 100%). We conclude that the combination of paclitaxel/cisplatin with weekly high-dose infusional 5-FU/LV appears to be effective in the first-line treatment of metastatic breast cancer. Preliminary results must be confirmed by the final analysis of response duration, time to progression, and survival.

Adult↗
PubMed1997

Cellular determinants of resistance to indolocarbazole analogue 6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13(beta-D-glucopyranosyl)- 5H-indolo[2,3-alpha]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (NB-506), a novel potent topoisomerase I inhibitor, in multidrug-resistant human tumor cells.

Membrane protein-associated alterations in cellular drug accumulation have been recently implicated in resistance to topoisomerase I (TOP-I)-interactive drugs. The present study investigated the cellular determinants of resistance to the indolocarbazole compound NB-506 [6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13(beta-D-glucopyranosyl)- 5H-indolo[2,3-alpha]pyrrolo[3,4-c]carbazole-5,7(6H)-dione], a structurally novel TOP-I-interactive drug, in parental and multidrug-resistant tumor cells expressing either the P-170 glycoprotein (Pgp170) or multidrug resistance protein (MRP). MRP-expressing 250-fold doxorubicin-resistant human fibrosarcoma HT1080/DR4 tumor cells were drug sensitive to NB-506 and camptothecin (CPT) (resistance factor: 0.7 and 0.8, respectively) with no alterations of TOP-I parameters including DNA relaxation, expression of TOP-I protein and mRNA. In contrast, doxorubicin-resistant human ovarian A2780/Dx5 tumor cells [pgp170 phenotype] were 6.2-fold resistant to NB-506, whereas resistance to CPT was 2.6-fold. HPLC analysis of cellular NB-506 accumulation showed no significant differences between A2780 and A2780/Dx5 cells (peak intracellular concentrations after 120-min exposure to 10 microM NB-506: 400+/-85.0 and 352+/-95.1 nmol NB-506/mg protein, respectively). However, resistant A2780/Dx5 cells expressed a lower amount of TOP-I mRNA and 29% protein levels of TOP-I compared to parental A2780 cells, resulting in decreased TOP-I catalytic activity (3.17+/-0.02 vs. 1.16+/-0.15 rel.U/microg nuclear protein) and reduced induction of NB-506-mediated cleavable complex formation in A2780/Dx5 cells. Furthermore, the lower induction of NB-506-induced protein-linked DNA breaks (PLDB) in A2780/Dx5 cells correlated with significantly decreased DNA 12.2-440 kb size fragmentation in these cells. The present study demonstrates that expression of MRP and Pgp170 does not confer resistance to NB-506. Resistance to indolocarbazole substance NB-506 in A2780/Dx5 cells was only related to downregulation of TOP-I associated with lower induction of cleavable complex formation and DNA fragmentation. The data reported herein may indicate that the new indolocarbazole compound NB-506 has potent antitumor efficacy in membrane-associated multidrug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

[CT angiography of the pulmonary artery in patients with bronchial carcinoma].

The aim of the study was to evaluate 3D computed tomography (3D-CT) for the visualization of tumor extent with respect to the infiltration of the pulmonary arteries in patients with locally advanced small and nonsmall-cell lung cancer. A total 61 examinations in 40 patients with bronchial carcinoma were performed with contrast-enhanced (150 ml injected with 4 ml/s after bolus tracking) 2 mm spiral CT (pitch 1.5, increment 1 mm) (Somatom Plus4, Siemens AG, Germany). Using the implemented software cine mode, surface shaded display (SSD), and maximum intensity projection (MIP), reconstructions of the pulmonary arteries and the tumors were generated. In comparison to conventional spiral thoracic CT, the optimized cross-sectional images of the mediastium represented a benefit with the technique described, and this can help to diagnose vessel infiltration and may therefore be of value for pre- and post-therapeutic staging in modern stage-adapted multimodality treatment programs.

Angiography↗
PubMed1997

DNA repair and cellular resistance to alkylating agents in chronic lymphocytic leukemia.

The time course of the formation and persistence of repair-induced DNA lesions such as single-strand breaks (SSBs) were determined in isolated lymphocytes derived from 32 patients with chronic lymphocytic leukemia (CLL) using the single-cell gel electrophoresis (SCGE, "comet") assay. After pulse-exposure to N-ethyl-N-nitrosourea (EtNU), the initial amount of SSBs (t0 SCGE values) and the time periods required to reduce DNA damage by 50% (t50% SCGE values) were determined in nuclear DNA of individual cells. The t0 SCGE and t50% SCGE values varied interindividually between CLL specimens by factors of 16.6 and 8.2, respectively. Regarding cell-to-cell variation, no major subpopulations with significantly different DNA repair capacities were observed in cell specimens from a given patient. In addition, a monoclonal antibody-based immunocytological assay was used to determine the elimination kinetics for the cytotoxic alkylation product O6-ethylguanine from nuclear DNA. A strong correlation was observed between the relative times for SSB repair and the elimination of O6-ethylguanine from nuclear DNA. Because SCGE and immunocytological assay measure different steps of DNA repair, this observation suggests coordinated regulation of the respective repair pathways. With regard to chemosensitivity profiles, a "fast" repair phenotype corresponded to enhanced in vitro resistance to EtNU, 1,3-bis(2-chloroethyl)-1-nitrosourea, or chlorambucil. Accelerated SSB repair and pronounced in vitro resistance to chlorambucil, 1,3-bis(2-chloroethyl)-1-nitrosourea, and EtNU were found in lymphocytes from CLL patients nonresponsive to chemotherapy with alkylating agents. Distinct DNA repair processes thus mediate resistance to alkylating agents in CLL lymphocytes.

Antineoplastic Agents, Alkylating↗
PubMed1996

Cloning and characterization of the MamI restriction-modification system from Microbacterium ammoniaphilum in Escherichia coli.

The genes encoding a class-IIN restriction-modification (R-M) system (MamI, sequence specificity [symbol: see text] from Microbacterium ammoniaphilum have been cloned in Escherichia coli. The vector used for cloning was plasmid pUC18 modified by the inclusion of three MamI recognition sites. Recombinant clones containing the mamIM gene in its genomic context became fully methylated in vivo and remained completely resistant against digestion with the R.MamI restriction endonuclease (ENase). Determination of the nucleotide (nt) sequence revealed three open reading frames with lengths of 1089 bp (ORF1), 276 bp (ORFc) and 927 bp (ORF2). On the basis of expression and deletion experiments, the 1089-bp ORF1 was assigned to mamIM encoding the M.MamI DNA methyltransferase (MTase). By amino acid sequencing of the N terminus of R.MamI and comparison of the deduced nt sequence with ORF2, the 927-bp ORF2 was identified as the mamIR gene encoding R.MamI. The 276-bp ORFc, located between mamIR and mamIM, is part of the DNA sequence downstream from mamIM shown to be necessary for controlled mamIM expression.

Amino Acid Sequence↗