Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metastasis tumor-associated 1 short form (MTA1s) is a naturally occurring, alternatively spliced variant of MTA1 that functions as a repressor of estrogen receptor (ER) alpha transcriptional functions, at least in part by binding and sequestering ERalpha in the cytoplasm. A unique C-terminal 33-amino acid region containing a nuclear receptor (NR)-box motif (-LRILL-) mediates binding of MTA1s with ERalpha and is indispensable in this interaction. Here, we elucidated the solution structure of this 33-amino acid region by NMR spectroscopy. We found a predominance of the alpha-helical region toward the N-terminal region, which includes the NR-box motif. In silico docking and comparison studies showed similarities between the NR-box motif of MTA1s and a similar motif of coregulators, both in structure and mode of ERalpha binding. In MCF-7 breast cancer cells, the MTA1s peptide effectively repressed ERalpha transactivation function, as evidenced by the estrogen response element-luc assay and down-regulation of estrogen-induced genes. In mechanistic studies, we found that the antiestrogenic effects of the MTA1s peptide were due to its ability to compete with the coactivator recruitment to ERalpha. Furthermore, the peptide efficiently repressed estrogen-induced proliferation and anchorage-independent growth of MCF-7 cells. In addition, the MTA1s peptide blocked the progression of tumors formed by MCF-7 cells overexpressing an ERalpha coactivator in a xenograft-based assay. In brief, the characterization of structure and antiestrogenic activity of MTA1s peptide highlight its therapeutic potential.
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PMID:Solution structure and antiestrogenic activity of the unique C-terminal, NR-box motif-containing region of MTA1s. 1680 47

Systemic chemotherapy is effective in only a subset of patients with metastasized colorectal cancer. Therefore, early selection of patients who are most likely to benefit from chemotherapy is desirable. Response to treatment may be determined by the delivery of the drug to the tumor, retention of the drug in the tumor and by the amount of intracellular uptake, metabolic activation and catabolism, as well as other factors. The first aim of this study was to investigate the predictive value of DCE-MRI with the contrast agent Gd-DTPA for tumor response to first-line chemotherapy in patients with liver metastases of colorectal cancer. The second aim was to investigate the predictive value of 5-fluorouracil (FU) uptake, retention and catabolism as measured by localized (19)F MRS for tumor response to FU therapy. Since FU uptake, retention and metabolism may depend on tumor vascularization, the relationship between (19)F MRS and the DCE-MRI parameters k(ep), K(trans) and v(e) was also examined (1). In this study, 37 patients were included. The kinetic parameters of DCE-MRI, k(ep), K(trans) and v(e), before start of treatment did not predict tumor response after 2 months, suggesting that the delivery of chemotherapy by tumor vasculature is not a major factor determining response in first-line treatment. No evident correlations between (19)F MRS parameters and tumor response were found. This suggests that in liver metastases that are not selected on the basis of their tumor diameter, FU uptake and catabolism are not limiting factors for response. The transfer constant K(trans), as measured by DCE-MRI before start of treatment, was negatively correlated with FU half-life in the liver metastases, which suggests that, in metastases with a larger tumor blood flow or permeability surface area product, FU is rapidly washed out from the tumor.
NMR Biomed 2007 Apr
PMID:Prediction of chemotherapeutic response of colorectal liver metastases with dynamic gadolinium-DTPA-enhanced MRI and localized 19F MRS pharmacokinetic studies of 5-fluorouracil. 1700 86

(1)H MRS is an attractive choice for non-invasively diagnosing brain tumours. Many studies have been performed to create an objective decision support system, but there is not yet a consensus as to the best techniques of MRS acquisition or data processing to be used for optimum classification. In this study, we investigate whether LCModel analysis of short-TE (30 ms), single-voxel tumour spectra provide a better input for classification than the use of the original spectra. A total of 145 histologically diagnosed brain tumour spectra were acquired [14 astrocytoma grade II (AS2), 15 astrocytoma grade III (AS3), 42 glioblastoma (GBM), 41 metastases (MET) and 33 meningioma (MNG)], and linear discriminant analyses (LDA) were performed on the LCModel analysis of the spectra and the original spectra. The results consistently suggest improvement in classification when the LCModel concentrations are used. LDA of AS2, MNG and high-grade tumours (HG, comprising GBM and MET) correctly classified 94% using the LCModel dataset compared with 93% using the spectral dataset. The inclusion of AS3 reduced the accuracy to 82% and 78% for LCModel analysis and the original spectra, respectively, and further separating HG into GBM and MET gave 70% compared with 60%. Generally MNG spectra have profiles that are visually distinct from those of the other tumour types, but the classification accuracy was typically about 80%, with MNG with substantial lipid/macromolecule signals being classified as HG. Omission of the lipid/macromolecule concentrations in the LCModel dataset provided an improvement in classification of MNG (91% compared with 76%). In conclusion, there appears to be an advantage to performing pattern recognition on the quantitative analysis of tumour spectra rather than using the whole spectra. However, the results suggest that a two-step LDA process may help in classifying the five tumour groups to provide optimum classification of MNG with high lipid/macromolecule contributions which maybe misclassified as HG.
NMR Biomed 2007 Dec
PMID:Linear discriminant analysis of brain tumour (1)H MR spectra: a comparison of classification using whole spectra versus metabolite quantification. 1732 43

The objectives of this study were to (a) explore the spectral characteristics of brain metastases, focusing on the origin of the primary cancer, and (b) evaluate the correlation with clinical outcome using multivariate analysis. High-resolution magic angle spinning (HR-MAS) MR spectra (n = 26) were obtained from 16 patients with brain metastases using a Bruker Avance DRX600 instrument. Standard pulse-acquired and spin-echo (TE 32 and 285 ms) (1)H spectra were obtained. These were examined using principal component analysis (PCA) and partial least squares regression analysis (PLS) relating spectral data to clinical outcome. The PCA score plot of pulse-acquired HR-MAS spectra showed a trend of clustering due to the origin of the metastases, mainly based on differences in the lipid signals at 1.3 and 0.9 ppm. With PLS, spectra of patients who died less than 5 months after surgery appeared to cluster in the lower left quadrant of the score plot. These preliminary results on brain metastasis classification and prediction of survival must be validated in a larger patient cohort. However, the possibility of differentiating metastases according to origin and predicting survival on the basis of HR-MAS spectra suggests that this method may be useful for diagnosing and planning treatment for brain metastases and also for guiding decisions about terminating further treatment.
NMR Biomed 2008 Feb
PMID:Characterization of brain metastases using high-resolution magic angle spinning MRS. 1754 42

The plexin family of transmembrane receptors are important for axon guidance, angiogenesis, but also in cancer. Recently, plexin-B1 somatic missense mutations were found in both primary tumors and metastases of breast and prostate cancers, with several mutations mapping to the Rho GTPase binding domain (RBD) in the cytoplasmic region of the receptor. Here we present the NMR solution structure of this domain, confirming that the protein has both a ubiquitin-like fold and surface features. Oncogenic mutations T1795A and T1802A are located in a loop region, perturb the average structure locally, and have no effect on Rho GTPase binding affinity. Mutations L1815F and L1815P are located at the Rho GTPase binding site and are associated with a complete loss of binding for Rac1 and Rnd1. Both are found to disturb the conformation of the beta3-beta4 sheet and the orientation of surrounding side chains. Our study suggests that the oncogenic behavior of the mutants can be rationalized with reference to the structure of the RBD of plexin-B1.
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PMID:Insights into oncogenic mutations of plexin-B1 based on the solution structure of the Rho GTPase binding domain. 1827 16

For a period of 12 years (1994-2005) we operated on 82 patients with malignant neoplasms in the soft tissues. We distributed the patients by the disease stage, localization and histology. Basically the patients underwent CAT, NMR, echography for affected proximate lymph nodes and X-ray of the lungs to check for distal metastases. With 42 of the tumors we performed precursory open biopsy and with 4 of the tumors we performed FNAB. FNAB is a cytological test not able to differentiate the tumor in detail, so subsequently we discontinued its application. 94 surgical operations including only one amputation were performed with 82 of the patients. The main methods of surgical intervention were the extended resections and excisions, but some more serious interventions had to be performed with differentiated localizations, such as the retroperitoneal liposarcomas (where sometimes other organs (kidney) had to be removed), breast sarcomas leading to mastectomies, shoulder area sarcomas requiring humeroscapular resections, stomach angiosarcomas resulting in subtotal resections etc. The histological variant, the tumor size and localization - either anatomical or in depth, are established and reported to be the main aggravating factors. The distinct resection lines during the operation and the presurgery planning after NMR turned out to be a very important prognostication sign. The 5-year survival period reaches 70%.
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PMID:[Treatment outcome of 82 patients with soft tissues sarcomas]. 1858 Aug 28

Metabonomic profiling using proton nuclear magnetic resonance ((1)H NMR) spectroscopy and multivariate data analysis of human serum samples was used to characterize metabolic profiles in renal cell carcinoma (RCC). We found distinct, easily detectable differences between (a) RCC patients and healthy humans, (b) RCC patients with metastases and without metastases, and (c) RCC patients before and after nephrectomy. Compared to healthy human serum, RCC serum had higher levels of lipid (mainly very low-density lipoproteins), isoleucine, leucine, lactate, alanine, N-acetylglycoproteins, pyruvate, glycerol, and unsaturated lipid, together with lower levels of acetoacetate, glutamine, phosphatidylcholine/choline, trimethylamine-N-oxide, and glucose. This pattern was somewhat reversed after nephrectomy. Altered metabolite concentrations are most likely the result of the cells switching to glycolysis to maintain energy homeostasis following the loss of ATP caused by impaired TCA cycle in RCC. Serum NMR spectra combined with principal component analysis techniques offer an efficient, convenient way of depicting tumour biochemistry and stratifying tumours under different pathophysiological conditions. It may be able to assist early diagnosis and postoperative surveillance of human malignant diseases using single blood samples.
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PMID:Metabonomic profiling of renal cell carcinoma: high-resolution proton nuclear magnetic resonance spectroscopy of human serum with multivariate data analysis. 1870 33

Chemotherapeutic treatment of neoplastic diseases is often restricted by adverse systemic toxicity, which limits the dose of drug that can be administered, or by the appearance of drug resistance. Therefore, novel targeted therapeutic approaches are being developed to improve current conventional therapy in order to increase specificity and biocompatibility, and decrease toxicity. Legumain represents a recently identified lysosomal protease that has been reported to be overexpressed in the majority of human solid tumors, to promote cell migration and is associated with enhanced tissue invasion and metastases. Therefore, it serves as a promising candidate for prodrug therapy. We synthesized a novel legumain-cleavable prodrug, carbobenzyloxy-alanine-alanine-asparagine-ethylenediamine-etoposide, which releases the chemotherapeutic agent, etoposide, as the active drug. The prodrug was characterized and analyzed by (1)H NMR and HPLC. 293 Human embryonic kidney (293 HEK) cells were stably transfected with human legumain, to achieve overexpression in vitro (293 HEK-Leg). 293 HEK-Leg cells expressed both active and inactive legumain and secreted it to the medium. Legumain expression was found to be elevated because of serum starvation in both 293 HEK cells and PC3 human prostate carcinoma cells. The commercial substrate of legumain, carbobenzyloxy-alanine-alanine-asparagine-amino-4-methyl coumarin (CBZ-Ala-Ala-Asn-AMC) and the synthesized prodrug were both cleaved by recombinant human legumain (rhlegumain) and legumain expressed in the 293 HEK-Leg cell lysate. Upon cleavage by rhlegumain, the prodrug showed an inhibitory effect on the proliferation of 293 HEK and 293 HEK-Leg cells. This study suggests a novel platform for prodrug therapy activated by legumain as a promising approach for cancer therapy.
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PMID:A novel antitumor prodrug platform designed to be cleaved by the endoprotease legumain. 1919 56

We describe a novel protocol for the non-histological diagnosis of human brain tumors in vitro combining high-resolution (31)P magnetic resonance spectroscopy ((31)P-MRS) of their phospholipid profile and statistical multivariate analysis. Chloroform/methanol extracts from 40 biopsies of human intracranial tumors obtained during neurosurgical procedures were prepared and analyzed by high-resolution (31)P-MRS. The samples were grouped in the following seven major classes: normal brain (n = 3), low-grade astrocytomas (n = 4), high-grade astrocytomas (n = 7), meningiomas (n = 9), schwannomas (n = 3), pituitary adenomas (n = 4), and metastatic tumors (n = 4). The phospholipid profile of every biopsy was determined by (31)P-NMR analysis of its chloroform/methanol extract and characterized by 19 variables including 10 individual phospholipid contributions and 9 phospholipid ratios. Most tumors depicted a decrease in phosphatidylethanolamine (PtdEtn) and phosphatidylserine (PtdSer), the former mainly in neuroepithelial neoplasms and the latter in metastases. An increase in phosphatidylcholine (PtdCho) and phosphatidylinositol (PtdIns) appeared predominantly in primary non-neuroepithelial tumors. Linear discriminant analysis (LDA) revealed the optimal combination of variables that could classify each biopsy between every pair of classes. The resultant discriminant functions were used to calculate the probability of correct classifications for each individual biopsy within the seven classes considered. Multilateral analysis classified correctly 100% of the normal brain samples, 89% of the meningiomas, 75% of the metastases, and 57% of the high-grade astrocytomas. The use of phospholipid profiles may complement appropriately previously proposed methods of intelligent diagnosis of human cerebral tumors.
NMR Biomed 2009 Jul
PMID:Assessment of 31P-NMR analysis of phospholipid profiles for potential differential diagnosis of human cerebral tumors. 1937 1

A combined strategy based on the development of pharmacophore hypotheses and NMR approaches is reported for the identification of novel inhibitors of heparanase, a key enzyme involved in tumor metastasis through the remodeling of the subepithelial and subendothelial basement membranes, resulting in the dissemination of metastatic cancer cells. Several pharmacophore hypotheses were initially developed from the most active heparanase inhibitors known to date and, after their application to a pool of 27 known heparanase inhibitors and a database of 1,120 compounds approved by the FDA, a four-point pharmacophore model was selected as the most predictive. This model was subsequently applied to a database of 686 chemical fragments, and a subset of 100 fragments accomplishing completely or partially the four-point model was selected to perform nuclear magnetic resonance experiments to validate the hypothesis. The experimental studies confirmed the reliability of our pharmacophore model, its applicability to in silico databases in order to reduce the number of compounds to be experimentally screened, and the possibility of generating fragment libraries enriched in heparanase inhibitors.
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PMID:Development and NMR validation of minimal pharmacophore hypotheses for the generation of fragment libraries enriched in heparanase inhibitors. 1942 20


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