title: Bacillus Calmette-Guerin improves local and systemic response to radiotherapy in invasive bladder cancer.
abstract: BACKGROUND
  A key factor contributing to radio-resistance in conservative invasive bladder cancer (BCa) treatment is tumor hypoxia and a strategy to overcome it is to trigger the production of nitric oxide (NO). On the other hand, ionizing radiation (IR) applied to a primary tumor can induce immunogenic cell death which may set off a cytotoxic immune response against the primary tumor and its metastasis.
  
  
  OBJECTIVE
  To study in vitro and in vivo, the role of BCG as a local sensitizer to overcome hypoxia-associated radio-resistance through the production of NO, and as an immune-stimulator to be used in combination with IR to generate a systemic response for invasive BCa treatment.
  
  
  METHODS
  We selected the invasive murine BCa cell line MB49-I which expresses inducible NO synthase and produces NO, cultured in vitro in 2D and 3D models, and inoculated in vivo in the subcutaneous of syngeneic mice.
  
  
  RESULTS
  in vitro, multicellular murine invasive spheroids mimicked in vivo central tumor necrosis. BCG pre-treatment radio-sensitized spheroids through the induction of NO production, while no effect was shown in monolayers. In vivo, not only did BCG improve the local response to IR but it also decreased the metastatic spread and promoted the development of abscopal effect/rejection of a second tumor.
  
  
  CONCLUSIONS
  Since BCG has already and successfully been used for the treatment of non-invasive BCa and it improves the response to ionizing radiation in invasive BCa, these results are translational relevant to be analyzed in patients with this pathology.
authors.affiliation: Fellowship of Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina; Universidad de Buenos Aires, Área Investigaciones, Instituto de Oncología "Ángel H Roffo", Argentina.
authors.forename: Barbara
authors.initials: B
authors.lastname: Prack Mc Cormick
authors.affiliation: Fellowship of Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina; Universidad de Buenos Aires, Área Investigaciones, Instituto de Oncología "Ángel H Roffo", Argentina.
authors.forename: Denise
authors.initials: D
authors.lastname: Belgorosky
authors.affiliation: Universidad de Buenos Aires, Área Investigaciones, Instituto de Oncología "Ángel H Roffo", Argentina.
authors.forename: Yanina
authors.initials: Y
authors.lastname: Langle
authors.affiliation: Fellowship of Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina; Universidad de Buenos Aires, Área Investigaciones, Instituto de Oncología "Ángel H Roffo", Argentina.
authors.forename: Natalia
authors.initials: N
authors.lastname: Balarino
authors.affiliation: Universidad de Buenos Aires, Área Investigaciones, Instituto de Oncología "Ángel H Roffo", Argentina.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Sandes
authors.affiliation: Universidad de Buenos Aires, Área Investigaciones, Instituto de Oncología "Ángel H Roffo", Argentina; Member of Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina. Electronic address: grupoeijan@gmail.com.
authors.forename: Ana María
authors.initials: AM
authors.lastname: Eiján
mesh_terms: D000818:Animals; D001500:BCG Vaccine / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*
chemical_list: D001500:BCG Vaccine; D011838:Radiation-Sensitizing Agents
keywords: Bacillus Calmette-Guerin (BCG); Invasive bladder cancer; In vivo-vaccine; Ionizing radiation; Radiosensitizer