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Thiopurines azathioprine and 6-mercaptopurine are effective immune-modulators and cytotoxic agents widely used in the treatment of autoimmune diseases, graft rejection, and cancer. Of concern is the growing epidemiologic evidence that chronic exposure to these agents increases the risk of mesenchymal and solid tumors. Although in vitro and in vivo animal studies suggest that these agents are mutagenic and have the potential to select for mismatch repair deficient mutants, their in vivo mechanism(s) of carcinogenicity in humans remain(s) unclear. We investigated the in vivo mutagenicity of thiopurines in a cross-sectional study of 119 children and adults with inflammatory bowel disease by determining the frequency and spectra of somatic mutations at the HPRT locus using the T-cell cloning assay. We observed a significant increase in the frequency of somatic mutations that was related to total dose (p<0.001) and duration of treatment (p<0.001) among 56 thiopurine treated subjects compared to 63 untreated subjects. By mutation spectra comparison of 1020 mutant isolates, we also observed a significant dose-dependent increase in the proportion of G:C to A:T transitions (p<0.001) that is consistent with the in vitro mutagenic signature of these drugs. Although in vivo selection for HPRT mutants may have confounded the absolute mutation frequency since this is a ratio value, the significant thiopurine dose-dependent correlations with frequency and mutation spectra shift strongly suggest that thiopurine treatment is mutagenic in vivo. We also investigated the prevalence of in vivo clonal proliferation by the combined analyses of HPRT mutations and TCRβ CDR3 regions from mutant isolates and observed a higher prevalence of cell proliferation in association with chronic thiopurine therapy. Thiopurine treated subjects displayed expansions of precursor or committed progenitor cells and post-β rearrangement thymocytes or mature T-cells while untreated adult subjects showed only post-β rearrangement expansions of thymocytes or mature T-cells. Thiopurine treated subjects also uniquely displayed clonal expansions of “hyper-mutable” thymocytes or mature T-cells that gave rise to progenies with independent mutations either through extensive proliferation or from genetic instability. This pattern predominated in children and exhibited the highest occurrences of G:C to A:T mutations. G:C to A:T transitions were also observed in both early precursors or committed progenitors and post-β rearrangement thymocytes or mature T-cells from thiopurine treated subjects compared to untreated subjects who displayed a low frequency of G:C to A:T mutations unrelated to thiopurine therapy in post-β rearrangement thymocytes or mature T-cells. These data provide direct evidence that thiopurine treatment is mutagenic in vivo by mutation induction that may be enhanced through its effects on cell proliferation, and provide the first mechanistic evidence for the carcinogenicity of these therapeutic agents in humans. Our observations also suggest the potential risks to proliferating precursor and mature cells. In children, we may be capturing a subpopulation of “hypermutable” T-cells with a higher propensity to progress to lymphoma, which occur at highest frequency following transplantation.

Crohn’s disease and Colitis, the two most common Inflammatory Bowel Diseases (IBD), are on the rise among young people. IBD symptoms include severe abdominal pain and frequent bowel movements, which can result in major dietary restrictions and delays in growth. IBD can also limit people’s physical activity, eating habits, and activities that are distant from a bathroom. Having IBD can be both limiting and embarrassing but little research has investigated the social and emotional implications of these diseases from a qualitative approach. Existing research fails to identify how stigma and dominant IBD discourses affect the lived experiences of people with IBD, young people in particular. IBD can create additional challenges for adolescents because it is perceived to threaten their normal development into healthy adults. The purpose of this project is to investigate how being young complicates the already difficult experience of being ill. I conducted interviews with three young people and a discursive analysis of official IBD resources for adolescents and found almost no descriptions of the actual experience of illness. Participants who engaged in photo-elicited interviews minimized the physical and emotional repercussions of having IBD. Informational resources designed for youth failed to address the severe physical and emotional pain of Crohn’s and Colitis. Instead, the available resources provided saccharine and arguably unrealistic depictions of IBD that deny young people a forum to express their own struggles. I compare my analysis of the interviews and IBD resources with my own experience and experiences presented in a zine. Analysis of both the interviews and the IBD resources reveals that young people with IBD can experience an embodied disappearance. Their bodies are smaller and weak, they retreat from social situations to avoid embarrassment, and their emotions are denied because they have no forums to be expressive. Finally, young people can experience a compounded disappearance because they are treated not for who they are but for what they should become. I argue that enabling young people the opportunity to speak candidly about the social conditions that contribute to their struggles could help them better understand, negotiate, and express their illness experiences / Thesis (Master, Kinesiology & Health Studies) -- Queen's University, 2011-08-09 10:39:24.603

Ulcerative colitis and Crohn's colitis are chronic inflammatory bowel diseases that occur with a high frequency in the North-East of Scotland. They are diseases of adolescents and young adults, although they may have their onset at any age. The aetiology is largely unknown. Oral sulphasalazine is used as the treatment of choice for the prevention of relapses. At present there is no satisfactory alternative and so, on present practice, patients may take the drug indefinitely after diagnosis of the disease. Inflammatory bowel disease itself does not increase the levels of sister chromatid exchange and micronuclei observed in the lymphocytes of the patients. Patients receiving sulphasalazine therapy, however, have significantly elevated levels of sister chromatid exchange and micronuclei in their lymphocytes compared to control individuals. In addition, patients show a significant elevation in sister chromatid exchange and micronuclei frequencies after commencing sulphasalazine therapy. The length of time on sulphasalazine is influential in determining the sister chromatid exchange frequency as is the acetylator phenotype of the patient. Sister chromatid exchange frequencies appear to remain elevated for many months after cessation of therapy, suggesting that the lesions produced by the sulphasalzine therapy are long-lived. <i>In vitro</i> studies have shown that sulphasalazine induces both sister chromatid exchange and micronuclei in human lymphocytes, whereas sulphapyridine and its acetylated metabolites induce only sister chromatid exchanges. 5-aminosalicylic acid, the active moiety of sulphasalazine, and its acetylated metabolite do not induce sister chromatid exchange or micronuclei at the concentrations tested. The present and future use of sulphasalazine therapy should be evaluated in light of these results, and the use of new drugs, based on the 5-aminosalicylic moiety should be encouraged to reduce the potential genetic risk to the patients.

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