Trans-sodium crocetinate enhancing survival and glioma response on magnetic resonance imaging to radiation and temozolomide

Laboratory investigation

View More View Less
  • Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia
Restricted access

Purchase Now

USD  $45.00

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00
Print or Print + Online

Object

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/m2/day for 5 days); 2) temozolomide and radiation therapy (8 Gy); or 3) TSC (100 μg/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 mm2 compared with 42.1 ± 2.7 mm2 in the temozolomide-alone group (p = 0.047) and 35.8 ± 5.1 mm2 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.

Abbreviations used in this paper: GB = glioblastoma; PBS = phosphate-buffered saline; TSC = trans-sodium crocetinate.

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00

Contributor Notes

Address correspondence to: Jason Sheehan, M.D., Ph.D., Box 800-212, Health Sciences Center, Charlottesville, Virginia 22908. email: jps2f@virginia.edu.

Please include this information when citing this paper: published online December 11, 2009; DOI: 10.3171/2009.11.JNS091314.

  • 1

    Abramoff MD, , Magelhaes PJ, & Ram SJ: Image processing with Image. J. Biophotonics International 11:3642, 2004

  • 2

    Barth RF: Rat brain tumor models in experimental neurooncology: the 9L, C6, T9, F98, RG2 (D74), RT-2 and CNS-1 gliomas. J Neurooncol 36:91102, 1998

    • Search Google Scholar
    • Export Citation
  • 3

    Barth RF, & Kaur B: Rat brain tumor models in experimental neuro-oncology: the C6, 9L, T9, RG2, F98, BT4C, RT-2 and CNS-1 gliomas. J Neurooncol 94:299312, 2009

    • Search Google Scholar
    • Export Citation
  • 4

    Burton EC, & Prados MD: Malignant gliomas. Curr Treat Options Oncol 1:459468, 2000

  • 5

    Butowski NA, , Sneed PK, & Chang SM: Diagnosis and treatment of recurrent high-grade astrocytoma. J Clin Oncol 24:12731280, 2006

  • 6

    Chapman JD, , Reuvers AP, , Borsa J, & Greenstock CL: Chemical radioprotection and radiosensitization of mammalian cells growing in vitro. Radiat Res 56:291306, 1973

    • Search Google Scholar
    • Export Citation
  • 7

    Chowdhury SK, , Laudicina D, , Blumenkrantz N, , Wirth M, & Alton KB: An LC/MS/MS method for the quantitation of MTIC (5-(3-N-methyltriazen-1-yl)-imidazole-4-carboxamide), a bioconversion product of temozolomide, in rat and dog plasma. J Pharm Biomed Anal 19:659668, 1999

    • Search Google Scholar
    • Export Citation
  • 8

    Coleman CN, & Turrisi AT: Radiation and chemotherapy sensitizers and protectors. Crit Rev Oncol Hematol 10:225252, 1990

  • 9

    Diringer MN: Hyperoxia: good or bad for the injured brain?. Curr Opin Crit Care 14:167171, 2008

  • 10

    Ezhilarasan R, , Mohanam I, , Govindarajan K, & Mohanam S: Glioma cells suppress hypoxia-induced endothelial cell apoptosis and promote the angiogenic process. Int J Oncol 30:701707, 2007

    • Search Google Scholar
    • Export Citation
  • 11

    Farrell CL, , Stewart PA, & Del Maestro RF: A new glioma model in rat: the C6 spheroid implantation technique permeability and vascular characterization. J Neurooncol 4:403415, 1987

    • Search Google Scholar
    • Export Citation
  • 12

    Fisher T, , Galanti G, , Lavie G, , Jacob-Hirsch J, , Kventsel I, & Zeligson S, : Mechanisms operative in the antitumor activity of temozolomide in glioblastoma multiforme. Cancer J 13:335344, 2007

    • Search Google Scholar
    • Export Citation
  • 13

    Friedman HS, , Dolan ME, , Pegg AE, , Marcelli S, , Keir S, & Catino JJ, : Activity of temozolomide in the treatment of central nervous system tumor xenografts. Cancer Res 55:28532857, 1995

    • Search Google Scholar
    • Export Citation
  • 14

    Gainer JL: Trans-sodium crocetinate for treating hypoxia/ischemia. Expert Opin Investig Drugs 17:917924, 2008

  • 15

    Gainer JL, , Stennett AK, & Murray RJ: The effect of trans sodium crocetinate (TSC) in a rat oleic acid model of acute lung injury. Pulm Pharmacol Ther 18:213216, 2005

    • Search Google Scholar
    • Export Citation
  • 16

    Giassi LJ, , Gilchrist MJ, , Graham MC, & Gainer JL: Trans-sodium crocetinate restores blood pressure, heart rate, and plasma lactate after hemorrhagic shock. J Trauma 51:932938, 2001

    • Search Google Scholar
    • Export Citation
  • 17

    Grobben B, , De Deyn PP, & Slegers H: Rat C6 glioma as experimental model system for the study of glioblastoma growth and invasion. Cell Tissue Res 310:257270, 2002

    • Search Google Scholar
    • Export Citation
  • 18

    Kang SG, , Kim JS, , Park K, , Kim JS, , Groves MD, & Nam DH: Combination celecoxib and temozolomide in C6 rat glioma orthotopic model. Oncol Rep 15:713, 2006

    • Search Google Scholar
    • Export Citation
  • 19

    Kaur B, , Tan C, , Brat DJ, , Post DE, & Van Meir EG: Genetic and hypoxic regulation of angiogenesis in gliomas. J Neurooncol 70:229243, 2004

    • Search Google Scholar
    • Export Citation
  • 20

    Khan N, , Li H, , Hou H, , Lariviere JP, , Gladstone DJ, & Demidenko E, : Tissue pO2 of orthotopic 9L and C6 gliomas and tumor-specific response to radiotherapy and hyperoxygenation. Int J Radiat Oncol Biol Phys 73:878885, 2009

    • Search Google Scholar
    • Export Citation
  • 21

    Kondziolka D, , Lunsford LD, , Claassen D, , Maitz AH, & Flickinger JC: Radiobiology of radiosurgery: Part I. The normal rat brain model. Neurosurgery 31:271279, 1992

    • Search Google Scholar
    • Export Citation
  • 22

    Korkolopoulou P, , Perdiki M, , Thymara I, , Boviatsis E, , Agrogiannis G, & Kotsiakis X, : Expression of hypoxia-related tissue factors in astrocytic gliomas. A multivariate survival study with emphasis upon carbonic anhydrase IX. Hum Pathol 38:629638, 2007

    • Search Google Scholar
    • Export Citation
  • 23

    Okonkwo DO, , Wagner J, , Melon DE, , Alden T, , Stone JR, & Helm GA, : Trans-sodium crocetinate increases oxygen delivery to brain parenchyma in rats on oxygen supplementation. Neurosci Lett 352:97100, 2003

    • Search Google Scholar
    • Export Citation
  • 24

    Proescholdt MA, , Mayer C, , Kubitza M, , Schubert T, , Liao SY, & Stanbridge EJ, : Expression of hypoxia-inducible carbonic anhydrases in brain tumors. Neuro Oncol 7:465475, 2005

    • Search Google Scholar
    • Export Citation
  • 25

    Roberts DA, , Detre JA, , Bolinger L, , Insko EK, & Leigh JS Jr: Quantitative magnetic resonance imaging of human brain perfusion at 1.5 T using steady-state inversion of arterial water. Proc Natl Acad Sci U S A 91:3337, 1994

    • Search Google Scholar
    • Export Citation
  • 26

    Rong Y, , Durden DL, , Van Meir EG, & Brat DJ: ‘Pseudopalisading’ necrosis in glioblastoma: a familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesis. J Neuropathol Exp Neurol 65:529539, 2006

    • Search Google Scholar
    • Export Citation
  • 27

    Saito R, , Bringas JR, , Panner A, , Tamas M, , Pieper RO, & Berger MS, : Convection-enhanced delivery of tumor necrosis factor-related apoptosis-inducing ligand with systemic administration of temozolomide prolongs survival in an intracranial glioblastoma xenograft model. Cancer Res 64:68586862, 2004

    • Search Google Scholar
    • Export Citation
  • 28

    Sheehan J, , Ionescu A, , Pouratian N, , Hamilton DK, , Schlesinger D, & Oskouian RJ Jr, : Use of trans sodium crocetinate for sensitizing glioblastoma multiforme to radiation: laboratory investigation. J Neurosurg 108:972978, 2008

    • Search Google Scholar
    • Export Citation
  • 29

    Sheehan J, , Sherman J, , Cifarelli C, , Jagannathan J, , Dassoulas K, & Olson C, : Effect of trans sodium crocetinate on brain tumor oxgenation. Laboratory investigation. J Neurosurg 111:226229, 2009

    • Search Google Scholar
    • Export Citation
  • 30

    Shrieve DC, , Klish M, , Wendland MM, & Watson GA: Basic principles of radiobiology, radiotherapy, and radiosurgery. Neurosurg Clin N Am 15:467479, x, 2004

    • Search Google Scholar
    • Export Citation
  • 31

    Spence AM, , Muzi M, , Swanson KR, , O'Sullivan F, , Rockhill JK, & Rajendran JG, : Regional hypoxia in glioblastoma multiforme quantified with [18F]fluoromisonidazole positron emission tomography before radiotherapy: correlation with time to progression and survival. Clin Cancer Res 14:26232630, 2008

    • Search Google Scholar
    • Export Citation
  • 32

    Stennett AK, , Dempsey GL, & Gainer JL: trans-Sodium crocetinate and diffusion enhancement. J Phys Chem B 110:1807818080, 2006

  • 33

    Stewart C, , Haitsma I, , Zador Z, , Hemphill JC III, , Morabito D, & Manley G III, : The new Licox combined brain tissue oxygen and brain temperature monitor: assessment of in vitro accuracy and clinical experience in severe traumatic brain injury. Neurosurgery 63:11591165, 2008

    • Search Google Scholar
    • Export Citation
  • 34

    Sugiyama S, , Yamashita Y, , Kikuchi T, , Sonoda Y, , Kumabe T, & Tominaga T: Enhanced antitumor effect of combined-modality treatment using convection-enhanced delivery of hydrophilic nitrosourea with irradiation or systemic administration of temozolomide in intracranial brain tumor xenografts. Neurol Res 30:960967, 2008

    • Search Google Scholar
    • Export Citation
  • 35

    Zagzag D, , Lukyanov Y, , Lan L, , Ali MA, , Esencay M, & Mendez O, : Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: implications for angiogenesis and glioma cell invasion. Lab Invest 86:12211232, 2006

    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 480 336 18
Full Text Views 173 17 2
PDF Downloads 40 7 1
EPUB Downloads 0 0 0