title: Combined cimetidine and temozolomide, compared with temozolomide alone: significant increases in survival in nude mice bearing U373 human glioblastoma multiforme orthotopic xenografts.
abstract: OBJECTIVE
  Malignant gliomas consist of both heterogeneous proliferating and migrating cell subpopulations, with migrating glioma cells exhibiting less sensitivity to antiproliferative or proapoptotic drugs than proliferative cells. Therefore, the authors combined cimetidine, an antiinflammatory agent already proven to act against migrating epithelial cancer cells, with temozolomide to determine whether the combination induces antitumor activities in experimental orthotopic human gliomas compared with the effects of temozolomide alone.
  
  
  METHODS
  Cimetidine added to temozolomide compared with temozolomide alone induced survival benefits in nude mice with U373 human glioblastoma multiforme (GBM) cells orthotopically xenografted in the brain. Computer-assisted phase-contrast microscopy analyses of 9L rat and U373 human GBM cells showed that cimetidine significantly decreased the migration levels of these tumor cells in vitro at concentrations at which tumor growth levels were not modified (as revealed on monotetrazolium colorimetric assay). Computer-assisted microscope analyses of neoglycoconjugate-based glycohistochemical staining profiles of 9L gliosarcomas grown in vivo revealed that cimetidine significantly decreased expression levels of endogenous receptors for fucose and, to a lesser extent, for N-acetyl-lactosamine moieties. Endogenous receptors of this specificity are known to play important roles in adhesion and migration processes of brain tumor cells.
  
  
  CONCLUSIONS
  Cimetidine, acting as an antiadhesive and therefore an antimigratory agent for glioma cells, could be added in complement to the cytotoxic temozolomide compound to combat both migrating and proliferating cells in GBM.
authors.affiliation: Department of Neurosurgery, Erasmus University Hospital, Belgium.
authors.forename: Florence
authors.initials: F
authors.lastname: Lefranc
authors.forename: Syril
authors.initials: S
authors.lastname: James
authors.forename: Isabelle
authors.initials: I
authors.lastname: Camby
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Gaussin
authors.forename: Francis
authors.initials: F
authors.lastname: Darro
authors.forename: Jacques
authors.initials: J
authors.lastname: Brotchi
authors.forename: Joachim
authors.initials: J
authors.lastname: Gabius
authors.forename: Robert
authors.initials: R
authors.lastname: Kiss
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000662:veterinary; D002927:Cimetidine / Q000008:administration & dosage / Q000494:pharmacology*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology / Q000662:veterinary; D051379:Mice; D008819:Mice, Nude; D000077204:Temozolomide; D014183:Transplantation, Heterologous
chemical_list: D000276:Adjuvants, Immunologic; D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D002927:Cimetidine; D000077204:Temozolomide