title: Cytotoxic chemotherapy upregulates pro-apoptotic Bax and Bak in the small intestine of rats and humans.
abstract: OBJECTIVE
  Small intestinal crypt cells rapidly undergo apoptosis in response to cytotoxic drug treatment that results in gastrointestinal toxicity. The Bcl-2 family have been implicated in both positive and negative regulation of intestinal cell apoptosis. The aim of this study was to examine the effect of cytotoxic treatment on Bcl-2 protein expression in patients and rats with tumours.
  
  
  METHODS
  Four pro- and four anti-apoptotic members of the Bcl-2 family, caspase-3 and p53 were examined in small intestinal crypts before and after treatment in rats and humans. Immunohistochemistry identified changes in protein expression over time, while relative RT-PCR was used to investigate mRNA expression in rat small intestine.
  
  
  RESULTS
  Cytotoxic treatment increased p53 and caspase-3 which coincided with elevated levels of apoptosis. Bax and Bak protein and mRNA expression also significantly increased at 6 hours following treatment in rats. Bax and Bak protein increased at day 1 after treatment in humans. Anti-apoptotic Mcl-1 protein decreased within 24hours. Other Bcl-2 family members showed only modest changes.
  
  
  CONCLUSIONS
  Increased expression of Bax and Bak but not other Bcl-2 family members is associated with apoptosis in small intestinal crypts and may amplify the sensitivity and susceptibility of crypt cells to chemotherapy-induced enteropathy.
authors.affiliation: Department of Medical Oncology, Royal Adelaide Hospital, Adelaide, South Australia. joanne.bowen@adelaide.edu.au
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Bowen
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Gibson
authors.forename: Dorothy M
authors.initials: DM
authors.lastname: Keefe
authors.forename: Adrian G
authors.initials: AG
authors.lastname: Cummins
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000187:drug effects*; D007414:Intestinal Neoplasms / Q000188:drug therapy; D008565:Membrane Proteins / Q000187:drug effects*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
chemical_list: D000970:Antineoplastic Agents; C494772:BAK1 protein, human; C494826:BAX protein, human; C494774:Bak1 protein, rat; C494828:Bax protein, rat; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases