Trans-sodium crocetinate enhancing survival and glioma response on magnetic resonance imaging to radiation and temozolomide.
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.
Sheehan
Jason
J
Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia, USA. jps2f@virginia.edu
Cifarelli
Christopher P
CP
Dassoulas
Kasandra
K
Olson
Claire
C
Rainey
Jessica
J
Han
Shaojie
S
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
D018906:Antineoplastic Agents, Alkylating; D011838:Radiation-Sensitizing Agents; C487773:trans-sodium crocetinate; D014801:Vitamin A; D002338:Carotenoids; D003606:Dacarbazine; D010100:Oxygen; D000077204:Temozolomide