Bacterial gene therapy - bactofection is a simple and effective method to deliver plasmid DNA into target tissue. We hypothesize that oral in vivo bactofection can be an interesting approach to influence the course of inflammatory bowel diseases. The aim of this study was to prove the effects of antioxidative and anti-inflammatory bactofection in dextran sulfate sodium (DSS)-treated mice. Attenuated bacteria Salmonella Typhimurium SL7207 carrying plasmids with genes encoding Cu-Zn superoxide dismutase and an N-terminal deletion mutant of monocyte chemoattractant protein-1 were prepared. Male Balb/c mice had ad libitum access to 1% DSS solution in drinking water during 10 days (mild model of colitis). The animals were daily fed with 200 Mio bacteria via gastric gavage during the experiment. Fecal consistency, clinical status, food and water intake were monitored. After 10 days samples were taken and markers of oxidative stress and inflammatory cytokine levels were measured. Colonic tissue was scored histologically by a blinded investigator. DSS treatment significantly increased the levels of inflammatory cytokines and malondialdehyde as a marker of lipoperoxidation in the colon. Anti-inflammatory gene therapy improved the total antioxidative capacity. In comparison with the untreated group, bacterial gene therapy lowered the histological colitis score. Salmonella-mediated antioxidative and anti-inflammatory gene therapy alleviated colitis in mice. The effect seems to be mediated by increased antioxidative status. Further studies will show whether recombinant probiotics expressing therapeutic gene might be used for the therapy of inflammatory bowel diseases.
Background and aims: The thiopurine drugs, azathioprine (AZA) and 6-mercaptopurine, are established in the treatment of infl ammatory bowel diseases (IBD). Polymorphisms in thiopurine S-methyltransferase (TPMT) gene have been associated with adverse drug reactions (ADRs) to AZA. Methods: The aim of this study was to evaluate TPMT polymorphisms and AZA-related toxicity in a Slovak cohort of 220 IBD patients treated with AZA. In every patient, the dose and duration of AZA therapy, concomitant 5-aminosalicylate (5-ASA) medication, frequency, type, time to onset, dose of ADR and concomitant 5-ASA at the onset of ADR were recorded. Each patient was also genotyped for the presence of variant TPMT alleles (*2,*3A,*3B,*3C). Frequency, type and circumstances of ADRs were compared according to TPMT status. Results: Of the 220 patients, 205 (93.2 %) were wild-type (TPMT*1/*1), one (0.5%) carried a TPMT*1/*3C allele, 13 (5.9 %) carried TPMT *1/*3A allele and one was homozygous for TMPT *3A allele. No TPMT *2 mutation was found. The incidence of adverse drug reactions was 62/205 (30.2 %) in the wild-type group as compared to 13/15 (86.7 %) in the TPMT mutation group, p=2.10-5. Leukopenia (WBC< 3.0*10^9/L) occurred in 21/205 (10.2 %) patients with wild type TPMT versus 11/15 (73.3 %) patients with TPMT mutations, p=0.000001. There was no signifi cant difference between TMPT groups in gastrointestinal or other ADRs. No impact of 5-ASA on the incidence and severity of AZA adverse drug reactions was observed. Conclusion: The incidence of leukopenia in TPMT mutant patients was signifi cantly higher and more severe as compared to TPMT wild type patients. We observed no impact of concomitant 5-ASA therapy on AZA induced toxicity (Tab. 4, Fig. 2, Ref. 37).
Abstract:Background: Thiopurine S-methyltransferase (TPMT) plays an important role in the metabolism of thiopurines. It has been suggested that TPMT genetic polymorphisms lead to dose-related hematopoietic toxicity. Since there are major ethnic differences in the prevalence of particular TPMT variants, it is important for each country to study their own prevalence in order to estimate the role of TPMT variants-related thiopurines toxicity in population suffering from particular infl ammatory bowel disease (IBD). Aims: The aim of this study was to determine the frequency of the four most common allelic variants of TPMT gene in the population of Slovak IBD patients. Methods: TPMT genetic polymorphisms (TPMT*2, TPMT*3A, TPMT*3B, TPMT*3C) were amplifi ed using PCR and consequently genotyped with genetic analyzer. The allele frequencies of particular allelic variants were calculated and compared with other Caucasian populations reported so far. Results: Three hundred and thirty IBD patients were included; 196/132/2 cases of Crohn´s disease/ulcerative colitis/unclassifi ed colitis; 180 (55 %) males. Ninety-three percent of patients were homozygous for wild-type TPMT variant. Heterozygous genotype of any of the studied polymorphisms was present in 6 % of patients while only one patient was homozygous for TPMT*3A allele (0.3 %). The most prevalent mutant allele was that of TPMT*3A (3.2 %). The distribution of most common allelic variants of TPMT gene among Slovak IBD patients was in accordance with previously reported prevalence in Caucasian populations. Conclusion: This study shows the prevalence of TPMT genetic polymorphisms in population of Slovak IBD patients. As in other Caucasian populations, the most common mutant allelic variant is that of TPMT*3A while the prevalence of homozygosity is relatively low (Tab. 3, Ref. 22). Full Text in PDF www.elis.sk.
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