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At least 19 recordsLinked to original sources
PubMed1984

Anti-tumour cytotoxin from macrophages: no correlation between cytotoxin adsorption by tumour cell lines and their cytotoxin susceptibility.

Mononuclear phagocytes can synthesize a cytotoxin, similar to that in tumour necrosis serum, which is cytotoxic to certain tumour cell lines in vitro. This study has investigated whether susceptibility and resistance to the cytotoxin can be explained in terms of the amount of cytotoxin receptor expressed on the tumour cell surface. Binding of cytotoxin has been quantitated both by direct adsorption and competitive inhibition assays with cytotoxin-resistant or -susceptible tumour lines and with sublines of susceptible lines, selected for resistance to the cytotoxin. For both rabbit and human cytotoxin, there was no correlation between cytotoxin adsorption by tumour cell lines and their cytotoxin susceptibility, suggesting that resistance to the cytotoxin is expressed at a post-receptor stage. Preliminary studies on the cytotoxin receptor of K562 cells have shown that it is probably not the transferrin receptor, and that protein but not carbohydrate is essential for its function.

Adsorption↗
PubMed2005

Adenoviral vector-mediated gene transfer of IL-13Ralpha2 chain followed by IL-13 cytotoxin treatment offers potent targeted therapy for cytotoxin-resistant cancers.

Previous studies demonstrated that IL-13Ralpha2 chain-overexpressing cancer cells were highly sensitive to IL-13 cytotoxin (IL13-PE38QQR) and could be targeted by cytotoxin treatment. However, the majority of human tumors do not express high levels of IL-13Ralpha2 chain. To expand the IL-13 cytotoxin-mediated cancer targeting therapy, we combined cytotoxin treatment with gene transfer of IL-13Ralpha2 chain. We constructed a recombinant adenoviral vector carrying the human IL-13Ralpha2 gene (Ad-IL-13Ralpha2), which expresses high levels of IL-13Ralpha2 chain on infected cells. Human cancer cell lines A549 and HOS, which originally show no IL-13Ralpha2 expression and little sensitivity to IL-13 cytotoxin, were effectively converted to become sensitive to this cytotoxin after Ad-IL-13Ralpha2 infection. The CC(50) of IL-13 cytotoxin for Ad-IL-13Ralpha2-infected A549 cells was <10 ng/ml, whereas the CC(50) for uninfected or control vector-infected cells was >500 ng/ml. We also examined the antitumor activity of IL-13 cytotoxin in an established xenograft model of cytotoxin-resistant human lung tumor. Only a single i.t. injection of Ad-IL-13Ralpha2 markedly enhanced the sensitivity of established tumors to IL-13 cytotoxin treatment; furthermore, this antitumor effect was significantly sustained for more than 1 month after the last treatment with IL-13 cytotoxin. Taken together, these results suggest the combination of adenoviral vector-mediated IL-13Ralpha2 gene transfer and IL-13 cytotoxin administration can be an effective targeting approach for several types of IL-13 cytotoxin-resistant cancers which show no or little expression of IL-13Ralpha2 chain.

Adenoviridae↗
PubMed1980

Interferon and cytotoxic factor (cytotoxin) released in the blood of mice infected with Mycobacterium bovis BCG. III. Interferon and cytotoxin induced by the specific antigen as compared with those induced by bacterial lipopolysaccharide.

The time course of development and decline of the ability of BCG-infected mice to produce interferon in the serum in response to the intravenous infection of purified protein derivative of tuberculin (PPD) was very similar to that of their systemic hypersensitivity to PPD. A cytotoxic factor (cytotoxin) was produced in parallel with interferon in the serum of BCG-infected mice after stimulation with PPD. The duration of the period in which cytotoxin-production responsiveness to PPD was definitely detectable was much shorter than that for interferon-production responsiveness although the periods for the maximum production of interferon and cytotoxin coincided. The kinetics of release of interferon in the serum of BCG-infected mice after stimulation with PPD did not parallel that of release of cytotoxin. The four kinds of activities, interferons and cytotoxins induced by PPD and lipopolysaccharide (LPS) in the serum of BCG-infected mice, were compared for their stability to heating at 56 C and to treatment at pH 2. The kinetics of inactivation of these four activities differed significantly, when the serum was either heated at 56 C or treated at pH 2. Interferon produced in response to LPS could be neutralized by anti-L cell(NDV) interferon rabbit serum as easily as L cell (NDV) interferon, 16 times as much antiserum was required to neutralize the same amount of interferon in response to PPD, but cytotoxins induced by PPD and LPS were not neutralized at all by the antiserum. From these findings it is thought likely that interferons and cytotoxins induced by PPD and LPS in the serum of BCG-infected mice are different substances, although the antigenic relationship between cytotoxins induced by PPD and LPS remains unknown.

Animals↗
PubMed1979

Interferon and cytotoxic factor (cytotoxin) released in the blood of mice infected with Mycobacterium bovis BCG. I. Enhanced production of interferon and appearance of cytotoxin stimulated by capsular polysaccharide of Klebsiella pneumoniae or bacterial lipopolysaccharide.

Interferon production stimulated by the active substance (neutral fraction) of the capsular polysaccharide of Klebsiella pneumoniae (neutral CPS-K) in BCG-infected mice was compared with that by bacterial lipopolysaccharide (LPS). Prior infection with BCG increased the responsiveness of mice to the lethal effect of neutral CPS-K as well as to that of LPS. Associated with this, BCG-infected mice showed a markedly enhanced ability to produce interferon after stimulation not only by LPS but also by neutral CPS-K. In addition, a cytotoxic factor (cytotoxin) was found to be released in the serum of BCG-infected mice after injection of these inducers. The kinetics of production of interferon and cytotoxin stimulated by neutral CPS-K were very similar to those stimulated by LPS. The time pattern of cytotoxin production was not in parallel with that of interferon production. Interferon reached a peak 2 hr and cytotoxin 3 hr after injection with these inducers. Interferon and cytotoxin produced by neutral CPS-K showed essentially the same stabilities to heating at 56 C and to treatment at pH 2 respectively as those produced by LPS. Interferon was inactivated by heating at 56 C more rapidly than cytotoxin. Cytotoxin was inactivated by treatment at pH 2 for 24 hr, whereas interferon activity was well preserved after this treatment. These results suggest that both activities are the result of different substances.

Animals↗
PubMed1994

Development of a tissue culture assay system for Campylobacter jejuni cytotoxin and the influence of culture conditions on cytotoxin production.

A tissue culture assay system to detect Campylobacter jejuni cytotoxin was developed, and the effect of culture conditions on cytotoxin production was examined. Broth-culture filtrates from clinical isolates were used. The expression of cytotoxicity was dependent on the presence of serum in the culture medium. Although the titre of cytotoxin was low, the greatest cytotoxicity was revealed when newborn calf (NCS), adult bovine or goat serum was added to minimum essential medium. Moderate or weak cytotoxicity was observed when fetal calf (FCS), swine or human serum was added, and no cytotoxicity was seen with the addition of horse, rabbit, cat or chicken serum. Furthermore, the cytotoxic titre in serum-free culture (SFC) for Chinese hamster ovary (CHO) cells was higher than that with serum supplementation. CHO cells showed the highest sensitivity in FCS, NCS and SFC assay systems, whereas HeLa, Vero, HEp-2 and Intestine 407 cells were sensitive only in the NCS assay. Brucella broth was excellent for cytotoxin production, but iron supplementation had no effect. Cytotoxic expression in the three assay systems differed between stationary and stirred cultures. Our results on cytotoxin production by reference strains of C. jejuni did not agree with the original reports. These findings suggest that several different cytotoxins may be produced by C. jejuni, and that the assay system may be important for the expression of cytotoxic activity.

Animals↗
PubMed1983

Cobra polypeptide cytotoxin I and marine worm polypeptide cytotoxin A-IV are potent and selective inhibitors of phospholipid-sensitive Ca2+-dependent protein kinase.

The effects of a number of polypeptide cytotoxins and neurotoxins on various protein kinases were examined. It was found that cobra cytotoxin I and marine worm cytotoxin A-IV effectively and specifically inhibited phospholipid-sensitive Ca2+-dependent protein kinase (PL-Ca-PK) relative to myosin light chain kinase and cyclic nucleotide-dependent protein kinases. Inhibition of PL-Ca-PK by these cytotoxins could be overcome by phosphatidylserine. Neurotoxins, in comparison, were much less effective inhibitors. The present findings indicated that these polypeptide cytotoxins, unlike other agents reported to date, were selective inhibitors of PL-Ca-PK and could be used to differentiate Ca2+-dependent events regulated by phospholipid or calmodulin.

Bee Venoms↗
PubMed1995

Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration.

Approximately 50% of Helicobacter pylori strains produce a cytotoxin, encoded by vacA, that induces vacuolation of eukaryotic cells. Analysis of a clinically isolated tox- strain (Tx30a) indicated secretion of a 93-kDa product from a 3933-base pair vacA open reading frame. Characterization of 59 different H. pylori isolates indicated the existence of three different families of vacA signal sequences (s1a, s1b, and s2) and two different families of middle-region alleles (m1 and m2). All possible combinations of these vacA regions were identified, with the exception of s2/m1 (p < 0.001); this mosaic organization implies that recombination has occurred in vivo between vacA alleles. Type s1/m1 strains produced a higher level of cytotoxin activity in vitro than type s1/m2 strains; none of 19 type s2/m2 strains produced detectable cytotoxin activity. The presence of cagA (cytotoxin-associated gene A) was closely associated with the presence of vacA signal sequence type s1 (p < 0.001). Among patients with past or present peptic ulceration, 21 (91%) of 23 harbored type s1 strains compared with 16 (48%) of 33 patients without peptic ulcers; only 2 (10%) of 19 subjects harboring type s2 strains had past or present peptic ulcers (p < 0.005). Thus, specific vacA genotypes of H. pylori strains are associated with the level of in vitro cytotoxin activity as well as clinical consequences.

Adult↗
PubMed1994

Conservation of the cytotoxin-associated (cagA) gene of Helicobacter pylori and investigation of association with vacuolating-cytotoxin activity and gastroduodenal disease.

Polymerase chain reaction (PCR) amplification and DNA hybridization analyses were used to test for the presence of the cytotoxin-associated (cagA) gene in 108 strains of Helicobacter pylori. Fifty-two geographically diverse strains of known vacuolating cytotoxin activity, and 56 recent UK clinical isolates from patients with duodenal ulceration (n = 28) and from healthy individuals who were endoscopically normal (n = 28) were studied. Overall, cagA was detected by PCR in 74 (69%) strains and DNA hybridization provided evidence of gene homologues in a further eight strains. For 96% of the cytotoxin-producing strains and 46% of the non-cytotoxin producing strains, there was a close association either with presence or absence of cagA. At the genomic level, Southern blot DNA hybridization showed that cagA was probably present in a single copy in most of the H. pylori tested, and that HaeIII restriction site variation within and around the gene provided additional markers of diversity for the species. As 40% of the cagA containing strains did not produce an active cytotoxin, and no significant association between cagA presence and DU-disease was observed, we concluded that the presence of the cagA gene in H. pylori could not be used as a single reliable predictor of higher risk patients.

Antigens, Bacterial↗
PubMed1988

Amino-acid sequences of four cytotoxins (cytotoxins I, II, III and IV) purified from the venom of the Thailand cobra, Naja naja siamensis.

Four cytotoxins, designated as cytotoxins I, II, III and IV, were isolated from the venom of the Thailand cobra (Naja naja siamensis) by gel filtration on Sephadex G-75 followed by CM-cellulose chromatography. The amino-acid sequences were determined by a combination of conventional methods. Cytotoxins I, II, III and IV were each composed of 60 amino-acid residues and their molecular weights were calculated to be 6693, 6646, 6709 and 6739, respectively. The amino-acid sequences were compared with those of cytotoxins from other cobra venoms already sequenced.

Amino Acid Sequence↗
PubMed1979

Interferon and cytotoxic factor (cytotoxin) released in the blood of mice infected with Mycobacterium bovis BCG. II. Influence of time after BCG inoculation on production of interferon and cytotoxin by capsular polysaccharide of Klebsiella pneumoniae or by bacterial lipopolysaccharide and on hyperreactivity to their lethal effects.

The time course of the occurrence of hyperreactivity in interferon and cytotoxin responses to the active substance (neutral fraction) of the capsular polysaccharide of Klebsiella pneumoniae (neutral CPS-K) and bacterial lipopolysaccharide (LPS) and of the hyperreactivity to their lethal effects was followed after infection with BCG in SMA and ICR strains of mice. The duration of these hyperreactivities of BCG-infected mice depended on the inoculum doses of BCG. The time patterns of the hyperreactivity to the lethal effects of neutral CPS-K and LPS were similar in both strains of mice, although the maximum toxicity of LPS by the intraperitoneal route in BCG-infected mice on a weight basis was stronger than that of neutral CPS-K. Irrespective of inducer and mouse strain, the time pattern of the hyperreactivity to produce cytotoxin was similar to that of the hyperreactivity to produce interferon. The patterns for these phenomena when neutral CPS-K was used as an inducer were also similar to those when LPS was used. In ICR mice the hyperreactivity in interferon and cytotoxin responses to either neutral CPS-K or LPS decayed significantly earlier than the hyperreactivity to their lethal effects, whereas in SMA mice the occurrence of both types of hyperreactivities seemed to be associated. Therefore, it is suggested that the mechanism for the hyperreactivity in interferon and cytotoxin responses to neutral CPS-K or LPS in BCG-infected mice is not necessarily the same as that for the hyperreactivity to their lethal effects.

Animals↗
PubMed1999

A novel cytotoxin from Clostridium difficile serogroup F is a functional hybrid between two other large clostridial cytotoxins.

The large clostridial cytotoxins (LCTs) constitute a group of high molecular weight clostridial cytotoxins that inactivate cellular small GTP-binding proteins. We demonstrate that a novel LCT (TcdB-1470) from Clostridium difficile strain 1470 is a functional hybrid between "reference" TcdB-10463 and Clostridium sordellii TcsL-1522. It bound to the same specific receptor as TcdB-10463 but glucosylated the same GTP-binding proteins as TcsL-1522. All three toxins had equal enzymatic potencies but were equally cytotoxic only when microinjected. When applied extracellularly TcdB-1470 and TcdB-10463 were considerably more potent cytotoxins than TcsL-1522. The small GTP-binding protein R-Ras was identified as a target for TcdB-1470 and also for TcsL-1522 but not for TcdB-10463. R-Ras is known to control integrin-extracellular matrix interactions from inside the cell. Its glucosylation may be a major determinant for the cell rounding and detachment induced by the two R-Ras-attacking toxins. In contrast, fibroblasts treated with TcdB-10463 were arborized and remained attached, with phosphotyrosine containing structures located at the cell-to-cell contacts and beta3-integrin remaining at the tips of cellular protrusions. These components were absent from cells treated with the R-Ras-inactivating toxins. The novel hybrid toxin will broaden the utility of the LCTs for clarifying the functions of several small GTPases, now including also R-Ras.

3T3 Cells↗
PubMed1994

Mutation of the cytotoxin-associated cagA gene does not affect the vacuolating cytotoxin activity of Helicobacter pylori.

Helicobacter pylori now is recognized as an etiological agent in chronic superficial gastritis and peptic ulcer disease. Although only about 60% of H. pylori isolates produce an immunodominant 128-kDa antigen (CagA; cytotoxin-associated gene product), virtually all H. pylori-infected patients with duodenal ulceration develop a serologic response to the 128-kDa protein, which suggests an association of this gene with ulceration. The cloned cagA gene from H. pylori 84-183 was disrupted by insertion of a kanamycin resistance gene, and this inactivated cagA construct was introduced into H. pylori 84-183 by electrotransformation. Southern hybridization of kanamycin-resistant H. pylori transformants demonstrated that the wild-type cagA gene had been disrupted by insertion of the kanamycin cassette, and immunoblot analysis showed that the mutant strains no longer produced the 128-kDa CagA protein. Similar results were obtained when the cagA mutation was introduced by natural transformation into H. pylori 60190, a high-level toxin-producing strain. The cagA-negative H. pylori strains showed cytotoxin, urease, and phospholipase C activities, C3 binding and adherence similar to those of the isogenic wild-type strains. These findings demonstrate that the cagA gene product does not affect the vacuolating cytotoxin activity of H. pylori.

Antigens, Bacterial↗
PubMed1999

Selective lysis of virus-infected cells by cobra snake cytotoxins: A sendai virus, human erythrocytes, and cytotoxin model.

By using a Sendai virus-human erythrocyte model, this work found that virus-infected cells were 10-fold more susceptible to lysis in two of five examined cobra venoms. Four cytotoxins were isolated from the venom of the cobra Naja nigricollis that also showed 10-fold higher cytotoxicity toward virus-infected cells than to untreated cells. As selective destruction of virus-infected cells is of immense importance in clinical practice, this work demonstrates the potential of cobra cytotoxins to serve as leading compounds for the generation of derivatives or fractions with high cytotoxic specificity toward virus-infected cells.

Animals↗
PubMed1996

The interrelationship between cytotoxin-associated gene A, vacuolating cytotoxin, and Helicobacter pylori-related diseases.

The interrelationship between cytotoxin-associated gene A (CagA), vacuolating cytotoxin (VacA), and Helicobacter pylori-related diseases was investigated in 155 H. pylori-infected patients. Four (7%) of 60 subjects had mixed cagA+ and cagA- H. pylori infections. The H. pylori isolates from 98.3% of 121 patients with anti-CagA antibodies were cagA+. The occurrence of cagA+ H. pylori among 76 patients with peptic ulcer disease (PUD) was higher (93.4%) than among 79 patients with functional dyspepsia (FD; 64.6%) (odds ratio [OR] = 7.80; P < .001). VacA+ isolates were isolated from 56.6% of the PUD patients and 35.4% of the FD patients (OR = 2.37; P = .0132). For type I (cagA+VacA+) isolates, these numbers were 56.6% and 31.6%, respectively (P = .003). Only 4% of the 71 VacA+ isolates were cagA-. In addition, 37% of the patients with PUD were infected with cagA+VacA- H. pylori. Chi 2 results did not improve when VacA was entered into the model in the presence of cagA, indicating that only cagA is associated with PUD.

Adult↗
PubMed1994

Nitrobenzyl mustard quaternary salts: a new class of hypoxia-selective cytotoxins capable of releasing diffusible cytotoxins on bioreduction.

PURPOSE: To explore the utility of a new class of compounds, nitrobenzyl mustard quaternary salts, as hypoxia-selective prodrugs of diffusible cytotoxins. METHODS AND MATERIALS: The parent compound N,N-bis(2-chloroethyl)-N-methyl-N-(2-nitrobenzyl)ammonium chloride (SN 25246) was prepared by reaction of 2-nitrobenzyl chloride with N-methyldiethanolamine, and reaction of the resulting quaternary diol with thionyl chloride at room temperature. The rate of release of mechlorethamine from this compound in the presence of cells under aerobic and hypoxic conditions was determined by trapping with diethyldithiocarbamate. Cytotoxicity was assessed by clonogenic assay of stirred suspension cultures of EMT6 cells, and also in intact and dissociated EMT6 spheroids. In vivo activity was evaluated in mice bearing SC KHT tumors. RESULTS: The parent compound is a stable, water-soluble compound with an E(1) of -369 mV. It releases mechlorethamine, and shows selective toxicity towards hypoxic EMT6 cells in culture, increasing with time to several 1000-fold after 4 h. It is much more active against intact than dissociated EMT6 spheroids, and shows low but statistically significant activity against KHT tumors in vivo. CONCLUSION: Nitrobenzyl mustard quaternary salts are a new class of hypoxia-selective cytotoxin. The parent compound shows very high selectivity for hypoxic cells in vitro, and undergoes reduction in hypoxic cells, releasing mechlorethamine which can back-diffuse to kill surrounding oxygenated cells.

Animals↗
PubMed2000

Genetic analysis and clinical evaluation of vacuolating cytotoxin gene A and cytotoxin-associated gene A in Taiwanese Helicobacter pylori isolates from peptic ulcer patients.

The aims of this study were to investigate the cytotoxin-associated gene A (cagA) and vacuolating cytotoxin gene A (vacA) subtype in Taiwanese H. pylori isolates from patients with gastroduodenal diseases and to assess the relationship between genotypes of isolates and clinical features. The vacA s1a allele was found in all isolates and vacA m1 allele was found in 15% of isolates. The cagA gene was found in 82.5% of isolates. The vacA s1a/m2 strains had a significantly higher prevalence rate than vacA s1a/m1 strains in Taiwan (p < 0.05). By aligning and comparing the nucleotide and amino acid sequences of vacA from the Taiwanese isolates, the signal sequence and N-terminal region were found to be highly conserved, but the middle region was found to be highly heterogeneous. Determining the relationship between the genotypes and clinical features, we found that the cagA gene was more closely associated with duodenal ulcer than with gastric ulcer and the vacA s1a/m2 strain was more closely associated with active chronic gastritis and atrophic gastritis than with chronic gastritis. Together, our results indicated that (i) the middle region of vacA gene in Taiwanese isolates was heterogeneous; (ii) s1a/m2 vacA strains had a high prevalence in Taiwanese peptic ulcers; and (iii) the cagA gene was significantly associated with duodenal ulcer.

Acute Disease↗
PubMed1995

Cloning and characterization of the cytotoxin L-encoding gene of Clostridium sordellii: homology with Clostridium difficile cytotoxin B.

Hybridization of an oligodeoxyribonucleotide (oligo) probe, designed from a repeated sequence ('oligo rep') at the C terminus of the Clostridium difficile (Cd) cytotoxin (Cyt), revealed that homologies exist between the Cd cyt gene and the genomes of several other clostridia, including Clostridium sordellii (Cs), suggesting a common ancestral cyt amongst the Clostridium genus. This Cd 'oligo rep' probe was used to clone the Cs (strain 6018) cyt. The sequenced (7095 bp) region encodes 2364 amino acids (aa) and corresponds to a protein of 270,614 Da. Cs Cyt has 76% identity with the Cd Cyt and 47% identity with the Cd enterotoxin (Ent). The latter third of the protein consists of repeated units, similar to those found for Cd Cyt. A highly conserved hydrophobic domain can be delineated. Few structural differences are evident between Cd and Cs Cyt to explain their different cellular and sub-cellular effects. A small open reading frame (ORF) encoding a protein of 16,484 Da is located 210 bp downstream from cyt. No homology was evident with any known sequence. The first 30 aa of this ORF may correspond to a signal peptide.

Amino Acid Sequence↗