Mutagenicity and potential carcinogenicity of thiopurine treatment in patients with inflammatory bowel disease.
The thiopurines azathioprine and 6-mercaptopurine (6-MP) are effective immune modulators and cytotoxic agents extensively used in the treatment of autoimmune diseases, graft rejection, and cancer. There is compelling epidemiologic evidence that thiopurine treatment increases the risk for a variety of tumors by mechanisms that are unclear. We investigated the in vivo mutagenicity of long-term thiopurine treatment by determining the frequency and spectra of somatic mutation events at the hypoxanthine phosphoribosyltransferase (HPRT) locus in peripheral T lymphocytes as well as the prevalence of mutant clonal proliferation in a cross-sectional analysis of data from 119 children and adults with inflammatory bowel disease (IBD). ANOVA and regression were performed to assess relationships among the frequency and spectra of HPRT mutations with disease, duration of illness, duration of treatment, and total therapeutic dose of azathioprine and 6-MP. We observed a significant increase in the frequency of somatic mutations in 56 subjects treated with thiopurines for IBD compared with 63 subjects not treated with thiopurines. This increase was related to both total dose (P < 0.001) and duration of treatment (P < 0.001). Comparative mutation spectra analysis of 1,020 mutant isolates revealed a significant increase in the proportion of all transitions (P < 0.001), particularly G:C to A:T transitions (P < 0.001). Combined analyses of two signatures for mutant clonality, HPRT mutation, and T-cell receptor beta CDR3 region unique gene sequence also showed a significant thiopurine-dependent increase in mutant cell clonal proliferation (P < 0.001). These findings provide in vivo evidence for mutation induction as a potential carcinogenic mechanism associated with chronic thiopurine intervention.
Nguyen
Truc
T
Department of Pediatrics, University of Vermont, Burlington, Vermont 05445-0068, USA.
Vacek
Pamela M
PM
O'Neill
Patrick
P
Colletti
Richard B
RB
Finette
Barry A
BA
D000328:Adult; D001379:Azathioprine / Q000009:adverse effects* / Q000627:therapeutic use; D002273:Carcinogens / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D003424:Crohn Disease / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use; D008213:Lymphocyte Activation; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects* / Q000627:therapeutic use; D009152:Mutagenicity Tests; D009153:Mutagens / Q000009:adverse effects; D009154:Mutation / Q000187:drug effects*; D012044:Regression Analysis; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology
D002273:Carcinogens; D007166:Immunosuppressive Agents; D009153:Mutagens; D015122:Mercaptopurine; D007041:Hypoxanthine Phosphoribosyltransferase; D001379:Azathioprine
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