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M Büchler

Publications and source records attributed to M Büchler.

At least 37 records · Page 2Linked to original sources
PubMed1998

Neurotensin receptors: a new marker for human ductal pancreatic adenocarcinoma.

BACKGROUND/AIMS: New imaging possibilities for early diagnosis of the devastating exocrine pancreatic adenocarcinomas would be highly welcome. Recently, pancreatic neuroendocrine tumours have been successfully visualised in vivo on the basis of their high density of receptors for the regulatory peptide somatostatin. Unfortunately, exocrine pancreatic tumours do not express sufficient amounts of somatostatin receptors. Therefore over-expression of other regulatory peptide receptors in these tumours needs to be found. METHODS: Receptors for the regulatory peptide neurotensin were evaluated in vitro by receptor autoradiography in 24 ductal pancreatic adenocarcinomas, 20 endocrine pancreatic cancers, 18 cases of chronic pancreatitis, and 10 normal pancreatic glands. RESULTS: Some 75% of all ductal pancreatic adenocarcinomas, most of them differentiated, were neurotensin receptor positive, whereas endocrine pancreatic cancers did not express neurotensin receptors. No neurotensin receptors were found in chronic pancreatitis or normal pancreatic tissues, including pancreatic acini, ducts, and islets. CONCLUSIONS: The selective and high expression of neurotensin receptors in ductal pancreatic adenocarcinomas could form the molecular basis for potential clinical applications, such as in vivo neurotensin receptor scintigraphy for early tumour diagnosis, radiotherapy with radiolabelled neurotensin analogues, and chemotherapy with neurotensin receptor antagonists.

Adenocarcinoma↗
PubMed1997

Cloning of novel transcripts of the human guanine-nucleotide-exchange factor Mss4: in situ chromosomal mapping and expression in pancreatic cancer.

In a previous large-scale analysis of gene expression in pancreatic cancer using gridded arrays of cDNA libraries and differential hybridizations, a gene that was a homolog to human mss4 was identified. Mss4 is a guanine-nucleotide-exchange factor for the Sec4/ Ypt1/Rab family of small GTP-binding proteins involved in the regulation of intracellular vesicular transport. By fluorescence in situ hybridization the human mss4 gene was assigned to chromosome 1q32-q41. Northern blot analysis revealed that three mss4 mRNA species are transcribed in human tissues of 780, 1200, and 2800 bp in length, respectively. Cloning and sequencing of the human mss4 transcripts from a pancreatic cancer cDNA library revealed that these mRNA species differ in the length of the 3-untranslated region and are probably due to the alternate use of polyadenylation sites. All mRNA species were detected at moderate to high levels in pancreatic cancer cell lines and were overexpressed in pancreatic cancer tissue compared to both normal pancreas and chronic pancreatitis tissue. However, the 1200-bp transcript was the Mss4 mRNA species with the highest level of expression in more than 50% of tumor cells and tissues. High levels of expression were found as well in other human tumor tissues. Mss4 as guanine-exchange factor required in the regulation of intracellular transport may be of importance for the function and growth of human tumor cells. However, the precise role of mss4 in human tumor cells is unknown and remains to be elucidated.

Amino Acid Sequence↗
PubMed1997

Characterization of a high copy number amplification at 6q24 in pancreatic cancer identifies c-myb as a candidate oncogene.

In a recent study designed to identify chromosomal aberrations in pancreatic cancer tissues using comparative genomic hybridization, a high copy number amplification on 6q was detected. To identify the most likely candidate oncogene, the extension of the amplification in pancreatic cancer tissues and cell lines was determined by Southern blot analysis. Exon trapping was performed with DNA from a yeast artificial chromosome clone containing the complete minimally amplified region. Only fragments from two genes, namely, the c-myb oncogene and a novel gene, were shown to be amplified. The c-myb proto-oncogene was amplified in 10% of the pancreatic carcinoma tissues and in the pancreatic cancer cell line PC2. Interestingly, the c-myb oncogene was overexpressed not only in the amplified samples but also in the majority of the examined pancreatic cancer tissues and cell lines, suggesting that amplification is only one of the mechanisms leading to overexpression. In contrast, the novel gene, which was called human eRF3b (eukaryotic release factor 3b), seems to be only coamplified with c-myb. Genetic alterations of c-myb were mainly found in advanced tumors, indicating a possible correlation to tumor progression and aggressive tumor phenotypes.

Adenocarcinoma↗
PubMed1997

Cloning of a gene highly overexpressed in cancer coding for a novel KH-domain containing protein.

In a previous large scale screen for differentially expressed genes in pancreatic cancer, we identified a gene highly overexpressed in cancer encoding a novel protein with four K-homologous (KH) domains. KH-domains are found in a subset of RNA-binding proteins, including pre-mRNA-binding (hnRNP) K protein and the fragile X mental retardation gene product (FMR1). By fluorescence in situ hybridization (FISH) the identified gene named koc (KH domain containing protein overexpressed in cancer) was assigned to chromosome 7p11.5. Two pseudogenes were localised on chromosome 6 and 11. The cloned koc cDNA has a 250 bp 5'-UTR, a 1740 bp ORF and a 2168 bp 3'-UTR. The AU-rich 3'-untranslated region of koc contains eight AUUUA and four AUUUUUA reiterated motifs. The deduced koc protein with 580 amino-acids has a relative molecular mass (Mr) of approximately 65,000 (65 K). The koc transcript is highly overexpressed in pancreatic cancer cell lines and in pancreatic cancer tissue as compared to both, normal pancreas and chronic pancreatitis tissue. High levels of expression were as well found in tissue samples of other human tumours. As the KH domain has been shown to be involved in the regulation of RNA synthesis and metabolism, we speculate that koc may assume a role in the regulation of tumour cell proliferation by interfering with transcriptional and or posttranscriptional processes. However, the precise role of koc in human tumour cells is unknown and remains to be elucidated.

Amino Acid Sequence↗
PubMed1997

Identification of genes with specific expression in pancreatic cancer by cDNA representational difference analysis.

cDNA representational difference analysis (cDNA-RDA) is a polymerase-chain-reaction-coupled subtractive and kinetic enrichment procedure for the isolation of differentially expressed genes. In this study, the technique was used to isolate novel genes specifically expressed in pancreatic cancer. cDNA-RDA was done on cDNA reverse transcribed from a poly(A)+ mRNA pool made from 10 cancer tissues (tester) by using as a driver a cDNA from a poly(A)+ mRNA pool made from a combination of 10 tissues of chronic pancreatitis and 10 healthy pancreatic tissues. The use of chronic pancreatitis in addition to healthy pancreas mRNA in the driver preparation eliminated the influence of stromal tissue components present as contamination in the cancer-specific preparations. Such cDNA-RDA led to the isolation of 16 distinct, cancer-specific gene fragments. These were confirmed to be overexpressed in pancreatic cancer tissues by Northern blot analysis. Sequence analysis revealed homologies to five genes previously implicated in the carcinogenesis of the pancreas or other tissues. Eleven fragments had no significant homology to any known gene and thus represent novel candidate disease genes. The experiments demonstrate that cDNA-RDA is a reproducible and highly efficient method for the identification of novel genes with cancer-specific expression.

Annexin A3↗
PubMed1997

Progress report. A randomized multicenter European study comparing adjuvant radiotherapy, 6-mo chemotherapy, and combination therapy vs no-adjuvant treatment in resectable pancreatic cancer (ESPAC-1).

CONCLUSION: The ESPAC-1 trial is the largest study of its kind in pancreatic cancer and should definitively address the question of the role of conventional methods of adjuvant treatment in pancreatic cancer. BACKGROUND: At the joint International Association of Pancreatology and the European Pancreatic Club meeting in Mannheim, Germany (June 12-15, 1996) a satellite meeting of the European Study Group for Pancreatic Cancer (ESPAC) met to discuss the progress of the ESPAC-1 trial. METHODS: A randomized multicenter study to address which, if any, of the following adjuvant treatments are of benefit in patients with resectable pancreatic cancer: radiotherapy (40 Gy with 5-FU as a sensitizing agent), 6 mo of chemotherapy (5-FU and folinic acid), or a combination of these treatments. RESULTS: From February 1994 to June 1996 (the time of the Mannheim meeting) 221 patients so far have been recruited into the three treatment arms and one control arm.

Adenocarcinoma↗
PubMed1997

Pathological changes in pancreatic ducts from patients with chronic pancreatitis.

CONCLUSION: Chronic pancreatitis and restricted pancreatic outflow are accompanied by pathological changes in the ducts, including inflammation and alterations in the microvasculature. These changes and loss of epithelium provide a likely explanation for increased release of serum proteins, immunoglobulins, and lactoferrin into the juice, and the possibility of luminal contents entering the extracellular space and bloodstream. BACKGROUND: Enlargement of pancreatic ducts is a well-known phenomenon accompanying chronic pancreatitis and conditions restricting outflow of pancreatic juice. However, the relationship between ductal pathology and concomitant changes in the pancreatic juice is incompletely understood. METHODS: Segments of pancreatic ducts removed at surgery from patients with chronic pancreatitis and conditions restricting outflow were studied by light and electron microscopy to assess the pathological changes. RESULTS: Pathological changes in ducts from patients with chronic pancreatitis include chronic inflammation in the wall, enlarged and numerous capillaries packed with erythrocytes and leukocytes close to the lumen, and loss of epithelium and sometimes basement membrane. Plasma cells provide a source for increased immunoglobulins. Ducts from patients with diseases restricting outflow show significant pathology.

Case-Control Studies↗
PubMed1997

The canalicular multidrug resistance protein, cMRP/MRP2, a novel conjugate export pump expressed in the apical membrane of hepatocytes.

The conjugate export pump in the hepatocyte canalicular membrane is, together with the ATP-dependent bile salt export pump, one of the two major pumps determining canalicular anion secretion and bile flow. The so-called bile salt-independent bile flow is largely driven by the cmrp/cmoat gene-encoded conjugate export pump, as indicated by the markedly reduced bile flow in the GY/TR- (11, 13-16) and the EHBR mutant rats (18-20). The importance of conjugation with glutathione (52, 53), glucuronate (11, 21), and sulfate (11, 16) for transfer of endogenous and xenobiotic substances from blood into bile has long been known. The molecular identification (7, 26, 54) and cloning (9, 10, 30) of the ATP-dependent export pump for these conjugates in the canalicular membrane was, at least in part, a consequence of the elucidation of the substrate specificity of the multidrug resistance protein (MRP) which is very similar to that of its canalicular isoform (3-6, 49). The broad substrate specificity of the conjugate export pump enables the terminal excretion of a multitude of conjugates and amphiphilic anions which are formed by a large number of relatively specific monooxygenases and transferases in phase I and phase II metabolism of endogenous and xenobiotic substances in the hepatocyte. The predominant expression of the conjugate export pump encoded by the cmrp/cmoat gene in the canalicular membrane does not exclude overexpression of this transporter in other cells and tissues when exposed to drugs and toxins that can be excreted by this pump. The apical conjugate export pump (8-10) may thus confer multidrug resistance to tumor cells in a similar manner as MRP1 (55). The observation that mRNA encoding rat cMrp/cMoat (10, 12) and its rabbit homolog (35) is not only detected in hepatocytes but also in small intestine and the kidneys suggests that the cmrp/cmoat gene-encoded conjugate export pump may function in the apical membrane domain of various epithelial cells.

Adenosine Triphosphate↗
PubMed1997

The impact of prostanoids on pulmonary gas exchange during abdominal surgery with mesenteric traction.

We investigated the effect of intravenous (iv) ibuprofen on prostanoid release and on pulmonary gas exchange after abdominal mesenteric traction (MT) during either abdominal aortic surgery or pancreas resection. In a prospective, randomized, double-blind study, 400 mg ibuprofen (pancreas n = 13, aorta n = 13) or a placebo (pancreas n = 13, aorta n = 13) was administered iv before skin incision. MT was applied uniformly. The prostanoid plasma concentrations, venous admixture (Q(va)/Q(t)), and PaO2/FIO2 ratio were determined at baseline (before MT) and 5, 15, 45, and 90 min after MT. Patients who underwent aortic surgery were older and exhibited a lower preoperative PaO2 than those who underwent pancreas resection. Placebo-treated patients revealed a 30-fold peak increase in 6-keto-prostaglandin F1alpha (stable metabolite of prostacyclin) levels after intentional MT during aortic as well as pancreatic operations. This response was accompanied by an increase in Q(va)/Q(t) (ibuprofen: pancreas 7% +/- 1%, aorta 14% +/- 2%; placebo: pancreas 16% +/- 3%, aorta 26% +/- 3%/15 min after MT [mean +/- SEM, P < 0.05, placebo vs ibuprofen]), which resulted in decreased PaO2/ FIO2 ratio only in the aortic surgery patients (ibuprofen: 310 +/- 19; placebo: 237 +/- 24 15 min after MT, [mean +/- SEM, P < 0.05]). The authors conclude that ibuprofen-pretreated patients demonstrated almost constant prostanoid levels without changes in pulmonary gas exchange after MT.

6-Ketoprostaglandin F1 alpha↗
PubMed1997

ESPAC-1 trial progress report: the European randomized adjuvant study comparing radiochemotherapy, 6 months chemotherapy and combination therapy versus observation in pancreatic cancer.

At the joint International Association of Pancreatology and European Pancreatic Club meeting at King's College, London (July 9-12, 1997), a satellite meeting of the European Study Group for Pancreatic Cancer (ESPAC) met to discuss the progress of the ESPAC-1 trial. This study will address which, if any, of the following adjuvant treatments are of benefit in patients with resectable pancreatic cancer: radiotherapy (40 Gy with 5-fluorouracil as a sensitising agent); 6 months chemotherapy (5-fluorouracil and folinic acid), or a combination of these treatments. The study, which commenced in 1994, had already recruited 348 patients into the 3 treatment arms and 1 control arm of the study by May 31, 1997. This is the largest study of its kind in pancreatic cancer and should definitively address the question of the role of conventional methods of adjuvant treatment in pancreatic cancer.

Chemotherapy, Adjuvant↗
PubMed1996

Identification of the biosynthetic leukotriene C4 export pump in murine mastocytoma cells as a homolog of the multidrug-resistance protein.

A membrane glycoprotein of 190 kDa has been identified previously by photoaffinity labeling as a candidate for the ATP-dependent export pump for leukotriene C4 in mastocytoma cells [Leier, I., Jedlitschky, G., Buchholz, U. & Keppler, D. (1994) Eur. J. Biochem. 220, 599-606]. The present study indicates that this protein represents the murine homolog of the human multidrug resistance protein (MRP). In immunoblot analyses several polyclonal anti-MRP antibodies and one monoclonal antibody recognized the protein of 190-kDa in plasma membranes of mastocytoma cells. Immunoprecipitation after photoaffinity labeling with [3H]leukotriene C4 precipitated the labeled 190-kDa glycoprotein. Deglycosylation by glycopeptide N-glycosidase F of mastocytoma membrane proteins was performed in comparison with membranes from MRP-overexpressing cells and resulted in a reduction of the molecular mass of 190 kDa by about 20 kDa in all membrane preparations. The expression of the murine mrp gene in the mastocytoma cells was analyzed by amplification and sequencing of two mrp cDNA fragments in the first nucleotide binding domain (182 bp) and in a domain proximal to the 3'-end (291 bp). The deduced amino acid sequences of these fragments were identical with murine Mrp and 86.7% and 89.7% identical with the corresponding sequences of human MRP. These results indicate that the ATP-dependent release of leukotriene C4 by murine mastocytoma cells is mediated by murine Mrp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

A pancreatic cancer-specific expression profile.

We present an approach making use of technology established in the context of the genome project to describe a pancreatic cancer-specific expression profile and to identify new potential disease genes or disease-associated-genes. By use of gridded arrays of pancreatic cancer cDNA libraries and differential hybridizations we show that 4% the gridded cDNA library clones contain sequences preferentially expressed in pancreatic cancer. EST-sequencing of 369 distinct (408 total), differentially expressed sequences identified novel genes (32.5%) or homologs to EST-sequences with unknown function (26.3%). Homologies to known genes allow to determine a pancreatic cancer-specific expression profile, which provides for the first time evidence for complex primary and secondary alterations of gene expression responsible for the development of the phenotype of pancreatic cancer cells. In addition this has led to the identification of novel differentially expressed genes, which represent potential oncogenes or disease-associated markers and may be helpful for the development of therapeutic or diagnostic modalities.

Animals↗