Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Topotecan, a water-soluble analogue of camptothecin, is a newly available cytotoxic agent which acts as an inhibitor of topoisomerase I, an enzyme necessary for DNA replication. Topotecan is a semisynthetic product derived from camptothecin, which was discovered during a National Cancer Institute cytotoxic drug screening program almost 30 years ago. It acts by forming a stable covalent complex with the DNA/topoisomerase I aggregate, the so-called 'cleavable complex'. This process leads to breaks in the DNA strand resulting in apoptosis and cell death. Topotecan possesses a serum half-life of approximately 3 h, a high volume of distribution with high tissue uptake and a low protein binding. The chemical structure is based on a lactone ring. Topotecan undergoes reversible hydrolysis from its biologically active lactone form to the open ring inactive carboxylate form. It is also able to penetrate the intact blood-brain barrier. Since most of the agent is excreted by the kidneys, dose adjustment is necessary when renal function is impaired. In contrast, pharmacokinetic behavior is unchanged in patients with limited hepatic function. The principal toxicity of topotecan when administered at standard doses is neutropenia, but thrombocytopenia and anemia occur as well, while the nonhematological toxicities are usually mild. Alopecia is frequently observed and some patients may suffer from pronounced fatigue. Most clinical data available are based on the following schedule: 1.5 mg/m2 topotecan given as a 30-min infusion, days 1-5. There are currently only minimal data available regarding a dose-antitumor activity relationship. Other topotecan administration schedules are currently being investigated. Preclinical data suggest that continuous-infusion schedules may be a better application form in terms of both, toxicity and antitumor activity. However, clinical trials could not confirm these results to date. Results of phase II studies suggest considerable antitumor activity of single agent topotecan in small cell lung cancer and ovarian cancer patients. A randomized phase III trial of topotecan versus paclitaxel in ovarian cancer patients pretreated with cisplatin/cyclophosphamide has demonstrated that topotecan is as effective as paclitaxel in the second-line treatment of these patients. Activity of topotecan was also observed in non-small-cell lung cancer, refractory leukemias/myelodysplastic syndromes and in childhood sarcomas. Due to its unique mechanism of action and lack of cross-resistance, cisplatin, etoposide, cytarabine and paclitaxel are potential interacting partners for combination chemotherapy regimens. However, the best combination regimen as well as the optimal combination schedule have yet to be conclusively determined. The potential of topotecan in a variety of solid tumors, as well as its use in combination regimens for ovarian and small cell lung cancer is currently being investigated.
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PMID:Topotecan - A novel topoisomerase I inhibitor: pharmacology and clinical experience. 988 71

A 57-year-old man presented with pneumonia, respiratory distress, and myelodysplastic syndrome. A diagnosis of Legionnaires' disease due to Legionella pneumophila (L. pneumophila) was established. The patient had long been drinking tap water via a conduit from a hot spring resource, from which L. pneumophila was also isolated. Both the patient's strain and the water strain of L. pneumophila were identified as serogroup 1, and the genetic relatedness between the two strains as seen by pulsed-field gel electrophoresis was 87%. The patient was successfully treated with erythromycin, fluoroquinolone, and rifampicin. This case raises an important issue on public health represented by legionellosis in Japan.
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PMID:Legionnaires' disease associated with habitual drinking of hot spring water. 1168 36

We investigated three small streams in the New Territories of Hong Kong, China. In each stream, we compared the benthic macroinvertebrate fauna of one site immediately upstream of an area of agricultural land (market gardening) with a second site immediately downstream. Each pair of sites was < 300 m apart. Samples were taken at the end of the dry season (March 2000) and again (April 2000) just after heavy rainfall had caused runoff from the fields. The total number of taxa at the downstream sites was the same as that in the upstream sites in March. In April, the total taxon richness was lower at the downstream localities although this difference was statistically significant in only one stream. The acute toxic effect of runoff became clearer when focusing on the group of sensitive benthic fauna. The grouping was done by ranking the relatively physiological tolerance to organotoxins following the relevant literature (Bull. Environ. Contam. Toxicol. 67 (2001) 360). All streams showed a significant downstream decrease in the number of sensitive taxa in April, while in two of three streams the number of relatively tolerant taxa increased. Ordination (by n-MDS) confirmed this pattern. It revealed a marked temporal trend in all streams resulting from a decrease of sensitive taxa downstream that was not apparent at the upstream sites. The size of the observed effects varied among streams, and may have reflected differences in the composition of the agricultural runoff.
Water Res 2002 Jul
PMID:The impact of agricultural runoff on stream benthos in Hong Kong, China. 1217 9

We used a biochemical approach based on the analysis of the quality and quantity of sedimentary organic matter for identifying new descriptors of the trophic state and environmental quality of coastal marine systems. A large-scale study, including 99 stations, belonging to 33 transects, was carried out along 250 km of the Apulian coasts (Mediterranean Sea) in March and September 2000. The investigated area covered a wide range of anthropogenic impacts (industrial ports, tourist harbours, areas affected by power plants and industrial wastes, mariculture areas). Other sites, including marine protected areas (i.e., without any apparent impact), were used as "control". Water column and benthic parameters provided different indications and classifications of the trophic state of coastal marine systems. We found that phytopigment content of the sediments changed in response to all different sources of anthropogenic impact and resulted in a useful descriptor of the trophic state and environmental quality. Highest sediment chlorophyll-a concentrations, indicating conditions of increasing eutrophication, were found in areas impacted by the discharge of heated waters from a power plant. In particular, the contribution of the autotrophic biomass to the biopolymeric carbon pool appeared to be a good descriptor of the decreasing environmental quality. Independently from the sampling period or the pollution source such contribution was significantly lower in transects subjected to anthropogenic impact than in control areas. Differences in trophic conditions were evident both in terms of quantity (i.e., total organic matter content) and quality (i.e., biochemical composition) of sediment organic matter. In particular, sediment protein concentration appeared to be a good descriptor of the trophic state of the benthic systems at different spatial scales. Multivariate (MDS) analysis allowed identifying areas characterised by hypertrophic, eutrophic and meso-oligotrophic conditions and to define relative threshold levels. A classification of the trophic state of coastal systems based on protein and carbohydrate concentrations is proposed.
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PMID:Assessing the trophic state and eutrophication of coastal marine systems: a new approach based on the biochemical composition of sediment organic matter. 1222 84

The accuracy of electron dose calculations performed by two commercially available treatment planning systems, Varian Cadplan and MDS Nordion Helax-TMS, were assessed. Three tests designed to reproduce clinical treatments likely to result in dose nonuniformity have been carried out. The tests examined oblique incidence of the electron beam; incidence on a surface containing a step shape; and incidence on a phantom containing a small air cavity. Dose calculations performed by the planning systems were compared with thermoluminescence dosimetry (TLD) measurements in a WTe electron solid water phantom. A Varian 2100C linear accelerator was used. In most situations, the discrepancy between calculated and measured dose was within the tolerance specified by the ICRU; however, some exceptions were noted. Helax-TMS produced errors of 5 mm in the position of the 10% isodose line in the penumbra of the obliquely incident beam. Both Cadplan and Helax-TMS overestimated the surface dose adjacent to a step in the beam entry surface by approximately 15%. An overestimation of 10% in dose was calculated by both systems downstream of the small air cavity. Discrepancies between the measured and calculated monitor units lay within the uncertainty limits of the measurements. In conclusion, calculations of absorbed dose from electron beams performed by Varian Cadplan and MDS Nordion Helax-TMS result in significant errors at shallow depths near surface irregularities and downstream of small air cavities.
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PMID:Electron dose calculations: a comparison of two commercial treatment planning computers. 1280 8

The purpose of this study is to perform a clinical evaluation of the first commercial (MDS Nordion, now Nucletron) treatment planning system for electron beams incorporating Monte Carlo dose calculation module. This software implements Kawrakow's VMC++ voxel-based Monte Carlo calculation algorithm. The accuracy of the dose distribution calculations is evaluated by direct comparisons with extensive sets of measured data in homogeneous and heterogeneous phantoms at different source-to-surface distances (SSDs) and gantry angles. We also verify the accuracy of the Monte Carlo module for monitor unit calculations in comparison with independent hand calculations for homogeneous water phantom at two different SSDs. All electron beams in the range 6-20 MeV are from a Siemens KD-2 linear accelerator. We used 10,000 or 50,000 histories/cm2 in our Monte Carlo calculations, which led to about 2.5% and 1% relative standard error of the mean of the calculated dose. The dose calculation time depends on the number of histories, the number of voxels used to map the patient anatomy, the field size, and the beam energy. The typical run time of the Monte Carlo calculations (10,000 histories/cm2) is 1.02 min on a 2.2 GHz Pentium 4 Xeon computer for a 9 MeV beam, 10 x 10 cm2 field size, incident on the phantom 15 x 15 x 10 cm3 consisting of 31 CT slices and voxels size of 3 x 3 x 3 mm3 (total of 486,720 voxels). We find good agreement (discrepancies smaller than 5%) for most of the tested dose distributions. We also find excellent agreement (discrepancies of 2.5% or less) for the monitor unit calculations relative to the independent manual calculations. The accuracy of monitor unit calculations does not depend on the SSD used, which allows the use of one virtual machine for each beam energy for all arbitrary SSDs. In some cases the test results are found to be sensitive to the voxel size applied such that bigger systematic errors (>5%) occur when large voxel sizes interfere with the extensions of heterogeneities or dose gradients because of differences between the experimental and calculated geometries. Therefore, user control over voxelization is important for high accuracy electron dose calculations.
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PMID:Evaluation of the first commercial Monte Carlo dose calculation engine for electron beam treatment planning. 1476 Oct 30

Recently, the water-soluble bifunctional alkylating agent treosulfan demonstrated broad stem cell toxicity, immunosuppressive as well as antileukemic activity. Due to its well known low non-hematologic toxicity profile, treosulfan was considered an alternative agent for conditioning prior to allogeneic transplantation. A first clinical study, combining 3 x 10 g/m2 of treosulfan with 5 x 30 mg/m2 of fludarabine, demonstrated the feasibility of this conditioning. A fast, reliable and complete development of the donor hematopoiesis was evident as well as a low non-hematologic toxicity, transplantation-related mortality and relapse rate. In a second study treosulfan was escalated from 3 x 10 to 3 x 12 and 3 x 14 g/m2. In this protocol, 55 pts (patients) not amenable to standard conditioning suffering from various hematological malignancies were included. Complete donor chimerism was reached by day 28 in 80% of the pts. So far, 8 pts (11%) died without disease progression and 11 pts (20%) relapsed. Treosulfan was very well tolerated. Especially no hepatic VOD, severe cardiac or pulmonary toxicity was noted. Acute GvHD (degrees 11-IV) occurred in 44% and chronic GvHD in 45% of pts. Considering the poor prognosis of these study populations, treosulfan-based conditioning is considered to be safe and efficient. New phase 11 clinical protocols in AML and MDS will be initiated.
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PMID:Treosulfan/fludarabine: a new conditioning regimen in allogeneic transplantation. 1512 79

New and improved methods have been developed to detect somatic and male-specific coliphages in large volumes of water by single agar layer (SAL), enrichment and membrane filter methods. Somatic coliphages were detected efficiently on E. coli hosts C and CN13, male-specific coliphages were detected more efficiently on E. coli Famp than on Salmonella typhimurium WG49 and both types of coliphages were detected simultaneously on E. coli C3000. For water volumes of up to 100 ml, the SAL method was efficient and reliable. For water volumes of <1 L and as many as 10 multiple 1 L volumes, the enrichment method was efficient in detecting very low numbers of coliphages. Membrane filter methods, in which coliphages were adsorbed to and eluted from filters, also were relatively efficient, but they were less efficient than SAL and enrichment methods and were considered to be more cumbersome. For filter adsorption-elution methods, coliphage recoveries were most efficient for cellulose ester filters, less efficient for electropositive 1 MDS filters and least efficient for a direct membrane filter method. Overall, the enrichment method was preferred because of its ability to easily and rapidly detect low levels of coliphages in large sample volumes by either presence-absence or most probable number quantification.
Water Sci Technol 2004
PMID:Development and evaluation of methods to detect coliphages in large volumes of water. 1531 11

A sheath-flow capillary electrophoresis-mass spectrometry (CE-MS) system utilizing a fully integrated large-bore stainless-steel emitter electrode tapered at the end for micro-ionspray operation has been developed and evaluated. A separation capillary with an outer diameter of up to 360 microm was inserted into the electrode thus forming a void volume of less than 15 nL between the capillary end and the electrospray ionisation (ESI) tip. The sheath liquid, usually methanol-water (80:20) with 0.1% formic acid for positive ion mode or methanol for negative ion mode, was delivered at 0.5-1.0 microL/min. Unlike previously reported CE-MS interfaces, the CE-MS probe was incorporated directly onto an Applied Biosystems/MDS SCIEX orthogonal-spray Turbo "V" ion source for ease of use and automatic operation. This integration enables fast and facile coupling and replacement of the separation capillary without interrupting the ion source configuration, and the sheath liquid supply. The reusable electrospray electrode was precisely fabricated and aligned with the length of the nebulizing gas tube for improved reproducibility. Automation was achieved through software control of both CE and tandem MS (MS/MS) for unattended batch sample analysis. The system was evaluated for attomole- to low femtomole-level profiling of model peptides and protein mixtures, bisphosphates, as well as antiviral nucleosidic drugs in cellular extracts.
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PMID:Design, optimisation, and evaluation of a sheath flow interface for automated capillary electrophoresis-electrospray-mass spectrometry. 1576 22

Topotecan (Hycamtin) is a water soluble semisynthetic analogue of the alkaloid camptothecin which has antitumour activity in preclinical models in vitro and in vivo. A range of Phase I studies has been performed and a daily x 5 iv. schedule, which showed most promising evidence of activity, was selected for extensive clinical evaluation. To date, topotecan has been shown to be active in a number of malignancies, including metastatic ovarian cancer, recurrent small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), breast cancer, colorectal cancer and myelodysplastic syndrome. In ovarian cancer, response rates of around 15% were identified in patients who had failed standard chemotherapy, and in a randomised, comparative study with paclitaxel response rates of 20% (topotecan) and 13% (paclitaxel) were observed. In addition, overall time to progression was impressive at 23 weeks (topotecan) compared with 14 weeks (paclitaxel). In recurrent SCLC, topotecan has shown good activity in sensitive patients with a response rate of 39%, although the response rate in refractory patients was considerably lower (7%). Median survival of all patients was 5.4 months, acceptable for this difficult clinical scenario. Topotecan is well-tolerated in the majority of patients and subjective toxicities are uncommon. The principal side-effect is myelosuppression, mainly neutropenia. Serious clinical sequelae are relatively uncommon and non-cumulative. Nonhaematological toxicities are generally mild and not dose-limiting. In clinical use, topotecan has exhibited activity in multiple tumour types, with a side-effect profile that is predictable and manageable. The drug is under evaluation in other tumour types and in combination chemotherapy regimens.
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PMID:Topotecan, an active new antineoplastic agent: review and current status. 1598 23


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