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W Voigt

Publications and source records attributed to W Voigt.

At least 37 records · Page 2Linked to original sources
PubMed1999

Ocular-adnexal lymphoid tumors: a clinicopathologic and molecular genetic study of 77 patients.

PURPOSE: To determine whether molecular genetic analysis of ocular-adnexal lymphoid tumors, combined with histopathology and tumor location, is helpful in predicting which patients will develop systemic lymphoma. METHODS: A combined retrospective and prospective study of 77 patients with ocular-adnexal lymphoid tumors was performed. The tumors were subdivided into conjunctival, orbital, and eyelid lesions, and all were studied using both routine histopathology and molecular genetic analysis. RESULTS: Most lesions (70%) were small cell lymphomas of the mucosa-associated lymphoid tissue type, and the majority of tumors (90%) contained monoclonal or oligoclonal populations of lymphocytes discovered on molecular genetic analysis. Additionally, 72% of tumors exhibiting clonality had more than one gene rearrangement. Fifty-three percent of patients developed extraocular lymphoma sometime during the course of their disease. Patients with gene rearrangements on Southern blot hybridization had a 52% incidence of nonocular disease, compared with 63% of those without rearrangements. Patients with conjunctival tumors had a 37.5% incidence of nonocular disease, those with orbital tumors had a 54% incidence, and those with eyelid tumors had a 100% incidence of nonocular lymphoma. Only two patients died as result of systemic lymphoma. CONCLUSIONS: Most ocular-adnexal lymphoid tumors are lymphomas of the mucosa-associated lymphoid tissue type. The majority of tumors exhibit gene rearrangements on molecular genetic analysis, and this technique was not helpful in predicting which patients would develop nonocular lymphoma. Tumor location did have predictive value: Conjunctival lesions had the lowest incidence of nonocular lymphoma, and lid lesions had the highest incidence. Even with disseminated disease, most patients have a favorable prognosis with treatment.

Adult↗
PubMed1998

Novel cellular determinants for reversal of multidrug resistance in cells expressing P170-glycoprotein.

The newly synthesized calcium channel blocker, Ro44-5912, significantly potentiates doxorubicin (Dox)-induced cytotoxicity at non-cytotoxic concentrations in Dox-resistant human ovarian cell line, A2780/DX5, overexpressing P170-glycoprotein (Pgp). Induction of DNA single- and double-strand breaks (ssbs and dsbs) was measured using alkaline elution and constant-field gel electrophoresis (CFGE) assays. The results indicate that potentiation of the cytotoxicity of Dox by Ro44-5912 was accompanied by significant increases in both, Dox-induced DNA ssbs and dsbs in the resistant cells. Pulsed-field gel electrophoresis (PFGE) analysis showed that Dox induced DNA fragments in the 50-800 kilobase (kb) and 0.8-5.7 megabase (Mb) ranges. The majority of the newly synthesized DNA fragments were in the 50-800 kb range. Ro44-5912 treatment resulted in significant potentiation of DNA fragmentation in the 50-800 kb range with a minor increase in 0.8-5.7 Mb DNA fragments, suggesting that the modulator functions by potentiating nascent DNA fragmentation in the resistant cells. Exposure to Dox with Ro44-5912 was associated with a prolonged blockage of cells in the S-phase. In contrast, exposure to Dox alone resulted in temporary blockage of cells in G2/M phase (approximately 24 h) followed by restoration of cell proliferation and normal DNA histograms at 48 h after 2 h drug exposure. Incorporation of BrdUrd by flow cytometric analysis was inhibited by Dox in the presence of Ro44-5912, showing that there is a block of DNA replication. An increased damage in newly synthesized DNA could concur with a blocked DNA replication. Moreover, slowing progression through the S-phase in cells exposed to Dox in combination with Ro44-5912 is accompanied by increased sensitivity of Dox poisons, indicating a correlation of specific S-phase perturbation with the reversal of Dox resistance by Ro44-5912 in cells expressing Pgp. The results suggest that drug-induced augmentation of nascent DNA fragmentation and specific cell-cycle perturbation are potentially important molecular determinants for reversal of multidrug resistance in addition to restoration of intracellular drug retention.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

p53 and WAF1 are induced and Rb protein is hypophosphorylated during cell growth inhibition by the thymidylate synthase inhibitor ZD1694 (Tomudex).

In a previous study, we found that treatment of HCT-8 cells with ZD1694, a specific antifolate-based thymidylate synthase inhibitor, resulted in DNA fragmentation. In this study, we have demonstrated the dose- and time-dependent induction of DNA fragmentation accompanied by elevation of p53 and WAF1 protein expression by ZD1694. WAF1 mRNA showed a time-dependent increase, whereas p53 mRNA was not found to be significantly overexpressed. The initial increase in WAF1 mRNA was detected at 4 hr, but increased WAF1 protein expression was detected 8-24 hr after a 2-hr exposure. The amount of total and hypophosphorylated pRb seems to be rising greatly after ZD1694 exposure. The effects of ZD1694 on the expression of E2F1 and formation of the E2F1-Rb complex were investigated after a 2-hr drug exposure (IC90). The results showed a time-dependent decrease in E2F1 mRNA and protein expression; an increase in the abundance of the E2F-Rb complex could be demonstrated beginning 4 hr after drug exposure by a gel shift assay. Kinetic analysis showed increased availability of hypophosphorylated pRb for inhibition of E2F, which could indirectly result from WAF1-induced inhibition cyclin-dependent kinase activity. Whereas thymidylate synthase inhibition by ZD1694 was rapid in onset and maintained for at least 24 hr after drug treatment, drug-induced cellular growth inhibition was significant 24 hr after drug exposure. The increased abundance of hypophosphorylated pRb and binding to transcription factor E2F-1 is consistent with ZD1694-induced cell growth inhibition in HCT-8 cells. Therefore, the observed effect on downstream events after effective inhibition of thymidylate synthase may offer the critical determinants of response to ZD1694.

Adenocarcinoma↗
PubMed1997

Characterization of urinary Escherichia coli O75 strains.

Forty-four Escherichia coli O75 strains from patients with urinary tract infections were characterized by a variety of methods to obtain evidence of their clonal distribution and uropathogenic properties. By K and H antigen typing, the strains were divided into the following serotypes: O75:K5:H- (18 strains), O75:K95:H- (10 strains), O75:K95:H5 (7 strains), O75:K100:H5 (4 strains), and O75:K-:H55 (5 strains). Generally, biotyping proved to be of no discriminative value. With two exceptions the strains were found to be sensitive to the bactericidal effect of normal human serum. As shown by multilocus enzyme electrophoresis, the whole-cell protein profile (WCPP), and the patterns of the outer membrane proteins and lipopolysaccharides, all but the five O75:H55 strains were genetically closely related to each other and could be classified into one clonal group. The O75:K-:H55 strains proved to be quite different and lacked type 1 fimbriae. All 17 K95 (H-, H5) strains produced hemolysin and P fimbriae. Five of the O75:K5:H- strains were different from the other K5 strains by showing hemagglutinating properties, on the basis of the presence of the OX adhesin. The last two groups are suggested to be uropathogenic and are proposed to represent separate clonal groups or subgroups.

Bacterial Typing Techniques↗
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↗
PubMed1996

Silibinin protects against cisplatin-induced nephrotoxicity without compromising cisplatin or ifosfamide anti-tumour activity.

Cisplatin is one of the most active cytotoxic agents in the treatment of testicular cancer, but its clinical use is associated with side-effects such as ototoxicity, neurotoxicity and nephrotoxicity. Long-term kidney damage from cisplatin particularly affects the proximal tubular apparatus and can be detected by increased urinary excretion of brush-border enzymes, such as L-alanine-aminopeptidase (AAP), and magnesium. In the current study, the flavonoid silibinin was used as a nephroprotectant for cisplatin-induced nephropathy in a rat animal model. Infusion of silibinin before cisplatin results in a significant decrease in glomerular (indicated by creatinine clearance and serum urea level) and tubular kidney toxicity (excretion of brush-border enzymes and magnesium). Silibinin given alone had no effect on renal function. In order to exclude an inhibition of the anti-tumour activity of cisplatin and 4-hydroperoxy-ifosfamide by co-administration of silibinin, in vitro studies were performed in three established human testicular cancer cell lines. Dose-response curves for cisplatin (3-30 000 nmol) combined with non-toxic silibinin doses (7.25 x 10(-6) or 7.25 x 10(-5) mol l-1) did not deviate significantly from those of cisplatin alone as measured by relative cell survival during a 5 day assay using the sulphorhodamine-B staining technique. Also silibinin did not influence the cytotoxic activity of 4-hydroperoxy-ifosfamide (30-10 000 nmol) in vitro. In summary, these in vitro data rule out a significant inhibition of the anti-tumour activity of the major nephrotoxic components, cisplatin and 4-hydroperoxy-ifosfamide, by co-administration of silibinin in a human germ cell tumour cell line model. Together with these demonstrated cytoprotection effects in the rat animal model, these data form the basis for a randomised clinical trial of silibinin for the protection of cisplatin-associated nephrotoxicity in patients with testicular cancer.

Animals↗
PubMed1996

Sequence analysis of the DNA binding domain of the estrogen receptor gene in ER (+)/PR (-) breast cancer.

Estrogen stimulates the proliferation of breast cancer cells and regulates the expression of other proteins, including the progesterone receptor (PR), via interaction with a unique estrogen receptor (ER), a ligand-inducible transcription factor that binds to regulatory DNA sequences associated with target genes. The best indirect evidence of an intact ER gene signaling system in a tumor is the demonstration of both ER and PR cytosol protein. The molecular basis of the ER (+)/PR (-) phenotype is unknown and may reflect either defective PR gene expression or alterations in the ER-specifically, inability of the ligand-receptor complex to effectively bind to regulatory sequences in DNA. To test the latter possibility, we evaluated 10 ER (+)/PR (-) resected human breast cancers for small deletions and point mutations in the DNA binding domain of the ER gene. Exons 2 and 3 and their flanking intron sequences were selectively amplified using the polymerase chain reaction and then directly sequenced using the Sanger dideoxynucleotide method. A normal gene sequence was found in all cases studied. We conclude that sequence aberrations in the DNA binding domain of the ER are not a common cause of absent PR expression in ER (+)/PR (-) breast carcinomas.

Breast Neoplasms↗
PubMed1995

Structural dependence of the allosteric interaction of semi-rigid verapamil analogues with dihydropyridine-binding in kitten heart.

Structural determinants of the allosteric interaction of semi-rigid verapamil analogues with dihydropyridine binding were investigated in kitten heart using [3H](+)-isradipine as radioligand. Chemical variations were performed in the alkyl chain of verapamil and include introduction of unsaturation (double or triple bonds) or the insertion of cyclohexyl moieties. Introduction of unsaturation generally reduces the allosteric interaction in the case of 'double bond'-and abolishes it in the case of 'triple bond'-derivatives. Also the introduction of cyclohexyl moieties diminishes the potency of allosteric interaction: derivatives with the phenylethylamino side chain in an equatorial position exhibit the allosteric interaction, while it is lacking in derivatives with the basic side chain in axial position. Thus, the reduced conformational flexibility of the new verapamil congeners reduces or abolishes their ability to allosterically interfere with dihydropyridine binding. A molecular interpretation was approached by molecular modelling studies. The strategy was to find low energy conformations common to the active congeners, but not shared by the inactive ones. Structural features discriminating allosterically active and inactive congeners comprise: 1) the position of the nitrogen, 2) the volume occupied by the N-methyl groups, 3) the direction of the N-H bond and 4) the position of the phenyl ring in the basic side chain.

Allosteric Site↗
PubMed1995

Genomic and biochemical relatedness between Vibrio cholerae serovar O139 and serovar O1 eltor strains.

Vibrio cholerae O139 (Bengal) the new pandemic cholera strain emerging on the Indian subcontinent has revealed considerable homology to Vibrio cholerae O1 EL Tor (strain of the seventh pandemic cholera) in terms of genetic and biochemical properties. Apart from capsule and O139 LPS formation, all strains of V. cholerae O139 were found to be identical to V. cholerae O1 EL Tor strains with respect to genomic restriction fragment length polymorphism, genomic distribution of the pathogenic island, pattern of OMP and multilocus enzymes. However, the analysis of a nonpathogenic V. cholerae O139 isolate from Sri Lanka with a totally different pattern of genetic properties underline that horizontal gene transfer of a piece of DNA encoding biosynthesis of the Vibrio cholerae O139-specific LPS and capsule formation to an O1 El Tor precursor strains must have occurred giving rise to a kind of hybrid V. cholerae O1 El Tor encoding the new serovar-specific O139 antigens.

Genome, Bacterial↗
PubMed1995

Contrasting patterns of DNA fragmentation induced by thymidylate synthase inhibitors, ZD1694 and AG-331.

The patterns of DNA fragmentation were evaluated following a brief exposure (2 h) of the human ileocecal adenocarcinoma cell line, HCT-8, to several specific thymidylate synthase inhibitors, a quinazoline (ZD1694) and benz[cd]indole-containing molecule (AG-331). The magnitude and size of DNA fragmentation induced by the two agents were assessed by alkaline elution for DNA single-strand breaks (ssbs), and by pulsed- and constant-field gel electrophoresis for DNA double-strand breaks (dsbs). Both agents induced dose-dependent DNA dsbs. While AG-331 induced ssbs and dsbs only in nascent DNA, ZD1694 affected both genomic and nascent DNA. The fragments of newly synthesized and genomic DNA, estimated by pulsed-field gel electrophoresis assay, were associated with the bands in the range of 0.05 to 1.1 and 1.1 to 5.7 megabases, respectively. 5-fluoro-2'-deoxyuridine (FdUrd), like ZD1694, produced both mature and nascent DNA fragmentation, whereas only nascent DNA breakage induced by 5-fluorouracil (FUra) was detected, similar to AG-331. The induction of both mature and nascent DNA fragmentation by ZD1694 and FdUrd appears to correlate with the higher, but similar, potency of these agents. Aphidicolin, a DNA polymerase inhibitor, protects from DNA dsbs and cytotoxicity by ZD1694 and AG-331. These observations suggest that replicative DNA synthesis is an important factor in ZD1694- and AG-331-induced DNA fragmentation and, subsequently, cell growth arrest. The results indicate that although the new antimetabolites investigated herein were developed and extensively evaluated as specific and potent thymidylate synthase inhibitors, DNA damage appears to be an important additional determinant of drug effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Antimetabolites, Antineoplastic↗
PubMed1994

Simultaneous expression of CD2 on a B-cell, small lymphocytic neoplasm.

An unusual neoplasm, best classified as a B-cell chronic lymphocytic leukemia on the basis of cytofluorographic, immunohistologic, and gene rearrangement analysis also co-expressed the T-cell associated marker CD2 (sheep erythrocyte receptor), but without other cell markers restricted to T cells. This case was associated with a more aggressive course than typically seen with B-CLL or malignant lymphoma, small lymphocytic type, implying along with previous reports that CD2 expression may serve as a marker of small lymphocytic tumor cell behavior and the ultimate clinical course. Thus, surface phenotypic analysis of these particular hematopoietic neoplasms may serve not only for identification of the malignancy, but could also render prognostic information.

Antigens, CD↗
PubMed1994

Application of physico-chemical typing methods for the epidemiological analysis of Salmonella enteritidis strains of phage type 25/17.

Eighty-nine Salmonella enteritidis phage type 25/17 strains isolated from a localized outbreak in the German state Nordrhein-Westfalen (outbreak NWI) could not be further differentiated by biochemotyping and plasmid pattern analysis. They were submitted to a complex typing system consisting of modern physico-chemical analytical procedures. In lipopolysaccharide pattern analysis the strains proved to be homogeneous. In multilocus enzyme electrophoresis, outer membrane and whole cell protein pattern (WCPP) analysis, and Fourier-transform infrared (FT-IR) spectroscopy (increasing extent of differentiation in the given order) strains deviating from each basal pattern were found. The extent of correspondence in these deviations was satisfactory. Forty-six strains of the same sero- and phage type, however, obtained from different outbreaks, were additionally typed. The results obtained with them indicate that the data of the first group were not restricted to strains from outbreak NWI, but of general validity. It was found that both WCPP and FT-IR represent valuable methods for the sub-grouping of bacteria.

Bacterial Outer Membrane Proteins↗
PubMed1994

[The value of urine phosphohexose isomerase activity in comparison with urine cytology. First diagnosis and tumor after-care in patients with cancer of the urinary bladder].

The importance of phosphohexose (PHI) activity in the urine of patients with carcinoma of the urinary bladder is examined on the basis of enzyme-histochemical studies in tumor cell homogenizates after transurethral resection for transitional cell carcinoma. The results gave rise to the question of whether the enzyme-histochemical activity patterns were reflected in the urine in the form of photometrically measurable activity, and thus whether the PHI activity can be used in screening as a marker to complement the standard urine cytological procedure. The sensitivity of PHI measurement was determined at 89%. The measurement of PHI in the urine of patients with an ileum neobladder or of patients with urinary tract infections does not provide any useful information.

Adult↗
PubMed1993

Nourseothricin (streptothricin) inactivated by a plasmid pIE636 encoded acetyl transferase of Escherichia coli: location of the acetyl group.

Escherichia coli strains harbouring the plasmid pIE636 are able to synthesize acetylcoenzyme A: streptothricin acetyltransferase (ACSAT). The (enzymatic) N-acetylation of streptothricin F is known to contribute significantly towards the loss of antibacterial activity. 13C-NMR analysis of [14C]N-acetyl-labelled streptothricin F, produced by ACSAT-catalysed acetylation of streptothricin F and subsequent purification by various chromatographical steps, unequivocally revealed streptothricin F to be acetylated at the beta-amino group (C16) (and not at the epsilon-amino group (C19)).

Acetylation↗
PubMed1993

Verapamil analogues with restricted molecular flexibility: synthesis and pharmacological evaluation of the four isomers of alpha-[1-[3-[N-[1- [2-(3,4-dimethoxyphenyl)ethyl]]-N-methylamino]cyclohexyl]]-alpha- isopropyl-3,4-dimethoxybenzene-acetonitrile.

The synthesis and pharmacological activities of the four isomeric racemates of alpha-[1-[3-[N-[1-[2-(3,4-dimethoxyphenyl)ethyl]]-N- methylamino]cyclohexyl]]-alpha-isopropyl-3,4-dimethoxybenzene-acetoni trile are reported (2a-d). The compounds are verapamil analogues with restricted molecular flexibility designed to gather information on the active conformation(s) of the parent drug. The relative stereochemistry of the four racemates was established by X-ray crystallography and by 1H NMR spectroscopy; conformational analysis was supported by theoretical calculations. Negative inotropic and chronotropic activities were evaluated on guinea pig atria, while vasodilatory activity on smooth muscle was tested on guinea pig aortic strips. Binding studies on cat ventricles were performed using (-)-[N-methyl-3H]desmethoxyverapamil (D888) as a reference ligand. The results seem to support the hypothesis that cardiac depressant and vasorelaxant activities are due to different conformations of the verapamil molecule.

Acetonitriles↗
PubMed1993

[Clonal spreading of a multidrug resistance Citrobacter freundii strain at a neonatal intensive care unit].

This paper reports on the epidemic spreading of a multiresistant Citrobacter (C.) freundii strain at a neonatal intensive care unit. A premature baby of the 27th week of pregnancy died from septic shock caused by this strain. According to the result of a statistical analysis of risk factors a connection between the colonization of neonates and the feeding with an enteral feeding tube was probably. This suspicion could be confirmed by the detection of the multiresistant strain in the infant formula. Plasmid analysis, examination of outer membrane proteins and lipopolysaccharides of these C. freundii strains demonstrated the identity of all isolates. The resistance to antibiotics of this multiresistant C. freundii clone was determined by a plasmid belonging to incompatibility group C with a molecular weight of 110 MDa. This plasmid was involved also in other nosocomial outbreaks. It persisted more than 7 years in the hospital flora of the intensive care unit.

Anti-Bacterial Agents↗
PubMed1992

Determination of hormonal response in uterine cancer cell lines by the ATP bioluminescence assay and flow cytometry.

Although progesterone receptor status has been shown to correlate with response to hormonal therapy, not all progesterone receptor-positive patients respond to this treatment and additional biologic assays are needed to help better predict clinical response to hormonal therapy. This study explored the potential of the ATP bioluminescence assay and flow cytometry as biological assays of hormonal response. Five uterine cancer cell lines were used: AE7, ECC-1, HEC1A, AN3, and SKUT1B. Cells were exposed to Provera or tamoxifen at 0.1, 0.2, 0.5, 1, 2, and 5X (X equal to peak plasma concentrations: 1.0 micrograms/ml Provera and 0.1 micrograms/ml tamoxifen). For correlation, estrogen and progesterone receptors were determined by the standard dextran-coated charcoal method. Only AE7 and ECC-1 were positive for progesterone receptors (501 fmol/mg AE7, 194 fmol/mg ECC-1) and the rest were negative (less than 8 fmol/mg). Tamoxifen exerted no inhibition to the above cell lines. Meanwhile, Provera exerted dose-response inhibition on both AE7 and ECC-1 cell lines. The effects of accumulation of G0-G1 phase and reduction of S, G2 cells (P less than 0.05), but not on the HEC1A cell line (P = 0.4). These changes confirmed the antiproliferative property of Provera. Further studies are needed to establish the role of the ATP bioluminescence assay and flow cytometry as biological assays of hormonal response.

Adenocarcinoma↗