title: Trans-sodium crocetinate enhancing survival and glioma response on magnetic resonance imaging to radiation and temozolomide.
abstract: OBJECTIVE
  Glioblastoma (GB) tumors typically exhibit regions of hypoxia. Hypoxic areas within the tumor can make tumor cells less sensitive to chemotherapy and radiation therapy. Trans-sodium crocetinate (TSC) has been shown to transiently increase oxygen to hypoxic brain tumors. The authors examined whether this improvement in intratumor oxygenation translates to a therapeutic advantage when delivering standard adjuvant treatment to GBs.
  
  
  METHODS
  The authors used C6 glioma cells to create a hypoxic GB model. The C6 glioma cells were stereotactically injected into the rat brain to create a tumor. Fifteen days later, MR imaging was used to confirm the presence of a glioma. The animals were randomly assigned to 1 of 3 groups: 1) temozolomide alone (350 mg/m(2)/day for 5 days); 2) temozolomide and radiation therapy (8 Gy); or 3) TSC (100 microg/kg for 5 days), temozolomide, and radiation therapy. Animals were followed through survival studies, and tumor response was assessed on serial MR images obtained at 15-day intervals during a 2-month period.
  
  
  RESULTS
  Mean survival (+/- SEM) of the temozolomide-alone and the temozolomide/radiotherapy groups was 23.2 +/- 0.9 and 29.4 +/- 4.4 days, respectively. Mean survival in the TSC/temozolomide/radiotherapy group was 39.8 +/- 6 days, a statistically significant improvement compared with either of the other groups (p < 0.05). Although tumor size was statistically equivalent in all groups at the time of treatment initiation, the addition of TSC to temozolomide and radiotherapy resulted in a statistically significant reduction in the MR imaging-documented mean tumor size at 30 days after tumor implantation. The mean tumor size in the TSC/temozolomide/radiotherapy group was 18.9 +/- 6.6 mm(2) compared with 42.1 +/- 2.7 mm(2) in the temozolomide-alone group (p = 0.047) and 35.8 +/- 5.1 mm(2) in the temozolomide/radiation group (p = 0.004).
  
  
  CONCLUSIONS
  In a hypoxic GB model, TSC improves the radiological and clinical effectiveness of temozolomide and radiation therapy. Further investigation of this oxygen diffusion enhancer as a radiosensitizer for hypoxic brain tumors seems warranted.
authors.affiliation: Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia, USA. jps2f@virginia.edu
authors.forename: Jason
authors.initials: J
authors.lastname: Sheehan
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Cifarelli
authors.forename: Kasandra
authors.initials: K
authors.lastname: Dassoulas
authors.forename: Claire
authors.initials: C
authors.lastname: Olson
authors.forename: Jessica
authors.initials: J
authors.lastname: Rainey
authors.forename: Shaojie
authors.initials: S
authors.lastname: Han
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D002338:Carotenoids; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004058:Diffusion; D004195:Disease Models, Animal; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D002534:Hypoxia, Brain / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D053208:Kaplan-Meier Estimate; D008279:Magnetic Resonance Imaging; D009368:Neoplasm Transplantation; D010100:Oxygen / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077204:Temozolomide; D014801:Vitamin A / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D011838:Radiation-Sensitizing Agents; C487773:trans-sodium crocetinate; D014801:Vitamin A; D002338:Carotenoids; D003606:Dacarbazine; D010100:Oxygen; D000077204:Temozolomide