title: Metformin plus temozolomide-based chemotherapy as adjuvant treatment for WHO grade III and IV malignant gliomas.
abstract: OBJECTIVE
  Glioblastoma multiforme (GBM) remains one of the most devastating diseases known to man and affects more than 17,000 patients in the United States alone every year. This malignancy infiltrates the brain early in its course and makes complete neurosurgical resection almost impossible. Recent years have brought significant advances in tumor biology, including the discovery that many cancers, including gliomas, appear to be supported by cells with stem-like properties. In the current study we have investigated the effects of combining metformin with the standard treatment-of-care, as this drug, already used in the treatment of diabetes mellitus, has shown surprising results in the treatment of breast cancer, being also associated with lower mortality in several other malignancies.
  
  
  METHODS
  The subjects of the current study were 8 patients with newly diagnosed high-grade gliomas, operated at the Department of Neurosurgery - Clinical University Emergency Hospital, Cluj Napoca. Tumor tissue cultures were established and characterized using immunofluorescence microscopy and PCR analysis and the sensitivity to metformin, epidermal growth factor (EGF) and temozolomide (TMZ) was tested. Microvascular density (MVD) assay was performed on the tumor samples.
  
  
  RESULTS
  Seven of the 8 cases had a positive correlation between the number of endothelial cells, the phenotype of isolated tumor cells and the response to adjuvant chemoradiotherapy. The isolated tumor cells had a stem-like behavior, being resistant to conventional drugs. In most cases there was no statistical significant difference between TMZ alone and TMZ plus EGF arms, but there was a important difference between TMZ alone and TMZ plus metformin arms in 6 of the cases.
  
  
  CONCLUSIONS
  New drugs and targeted molecular therapies are important for future therapeutics, but sometimes we must not exclude drugs already used in the clinic that might have remarkable results. Such is the case of metformin, a drug used for decades in the treatment of type 2 diabetes mellitus that has proven to enhance the effect of TMZ in the treatment of breast cancer and, starting with this paper, of brain cancer.
authors.affiliation: Department of Cancer Immunology, Ion Chiricuta Oncology Institute, Cluj Napoca, Cluj Napoca, Romania.
authors.forename: O
authors.initials: O
authors.lastname: Soritau
authors.forename: C
authors.initials: C
authors.lastname: Tomuleasa
authors.forename: M
authors.initials: M
authors.lastname: Aldea
authors.forename: B
authors.initials: B
authors.lastname: Petrushev
authors.forename: S
authors.initials: S
authors.lastname: Susman
authors.forename: D
authors.initials: D
authors.lastname: Gheban
authors.forename: H
authors.initials: H
authors.lastname: Ioani
authors.forename: A
authors.initials: A
authors.lastname: Cosis
authors.forename: I
authors.initials: I
authors.lastname: Brie
authors.forename: A
authors.initials: A
authors.lastname: Irimie
authors.forename: G
authors.initials: G
authors.lastname: Kacso
authors.forename: I S
authors.initials: IS
authors.lastname: Florian
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007124:Immunoenzyme Techniques; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D009367:Neoplasm Staging; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D000077204:Temozolomide; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D014944:World Health Organization
chemical_list: D018906:Antineoplastic Agents, Alkylating; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D003606:Dacarbazine; D008687:Metformin; D000077204:Temozolomide