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BMC Cancer
Published in: BMC Cancer 1/2013

Open Access 01-12-2013 | Research article

The prospective application of a hypoxic radiosensitizer, doranidazole to rat intracranial glioblastoma with blood brain barrier disruption

Published in: BMC Cancer | Issue 1/2013

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Abstract

Background

Glioblastoma is one of the intractable cancers and is highly resistant to ionizing radiation. This radioresistance is partly due to the presence of a hypoxic region which is widely found in advanced malignant gliomas. In the present study, we evaluated the effectiveness of the hypoxic cell sensitizer doranidazole (PR-350) using the C6 rat glioblastoma model, focusing on the status of blood brain barrier (BBB).

Methods

Reproductive cell death in the rat C6 glioma cell line was determined by means of clonogenic assay. An intracranial C6 glioma model was established for the in vivo experiments. To investigate the status of the BBB in C6 glioma bearing brain, we performed the Evans blue extravasation test. Autoradiography with [14C]-doranidazole was performed to examine the distribution of doranidazole in the glioma tumor. T2-weighted MRI was employed to examine the effects of X-irradiation and/or doranidazole on tumor growth.

Results

Doranidazole significantly enhanced radiation-induced reproductive cell death in vitro under hypoxia, but not under normoxia. The BBB in C6-bearing brain was completely disrupted and [14C]-doranidazole specifically penetrated the tumor regions. Combined treatment with X-irradiation and doranidazole significantly inhibited the growth of C6 gliomas.

Conclusions

Our results revealed that BBB disruption in glioma enables BBB-impermeable radiosensitizers to penetrate and distribute in the target region. This study is the first to propose that in malignant glioma the administration of hydrophilic hypoxic radiosensitizers could be a potent strategy for improving the clinical outcome of radiotherapy without side effects.
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Literature
1.
Burton EC, Prados MD: Malignant gliomas. Curr Treat Options Oncol. 2000, 1 (5): 459-468. 10.1007/s11864-000-0073-2.CrossRefPubMed
2.
Forsyth PA, Cairncross JG: Treatment of malignant glioma in adults. Curr Opin Neurol. 1995, 8 (6): 414-418. 10.1097/00019052-199512000-00002.CrossRefPubMed
3.
Robins HI, Chang S, Butowski N, Mehta M: Therapeutic advances for glioblastoma multiforme: current status and future prospects. Curr Oncol Rep. 2007, 9 (1): 66-70. 10.1007/BF02951428.CrossRefPubMed
4.
Jensen RL: Brain tumor hypoxia: tumorigenesis, angiogenesis, imaging, pseudoprogression, and as a therapeutic target. J Neurooncol. 2009, 92 (3): 317-335. 10.1007/s11060-009-9827-2.CrossRefPubMed
5.
Chakravarti A, Dicker A, Mehta M: The contribution of epidermal growth factor receptor (EGFR) signaling pathway to radioresistance in human gliomas: a review of preclinical and correlative clinical data. Int J Radiat Oncol Biol Phys. 2004, 58 (3): 927-931. 10.1016/j.ijrobp.2003.09.092.CrossRefPubMed
6.
Baumann M, Krause M, Hill R: Exploring the role of cancer stem cells in radioresistance. Nat Rev Cancer. 2008, 8 (7): 545-554.CrossRefPubMed
7.
Brown JM, Wilson WR: Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer. 2004, 4 (6): 437-447. 10.1038/nrc1367.CrossRefPubMed
8.
9.
Brat DJ, Mapstone TB: Malignant glioma physiology: cellular response to hypoxia and its role in tumor progression. Ann Intern Med. 2003, 138 (8): 659-668.CrossRefPubMed
10.
Nagasawa H, Uto Y, Kirk KL, Hori H: Design of hypoxia-targeting drugs as new cancer chemotherapeutics. Biol Pharm Bull. 2006, 29 (12): 2335-2342. 10.1248/bpb.29.2335.CrossRefPubMed
11.
Overgaard J: Hypoxic radiosensitization: adored and ignored. J Clin Oncol. 2007, 25 (26): 4066-4074. 10.1200/JCO.2007.12.7878.CrossRefPubMed
12.
Kaanders JH, Bussink J, van der Kogel AJ: Clinical studies of hypoxia modification in radiotherapy. Semin Radiat Oncol. 2004, 14 (3): 233-240. 10.1016/j.semradonc.2004.04.002.CrossRefPubMed
13.
Overgaard J, Hansen HS, Andersen AP, Hjelm-Hansen M, Jorgensen K, Sandberg E, Berthelsen A, Hammer R, Pedersen M: Misonidazole combined with split-course radiotherapy in the treatment of invasive carcinoma of larynx and pharynx: report from the DAHANCA 2 study. Int J Radiat Oncol Biol Phys. 1989, 16 (4): 1065-1068. 10.1016/0360-3016(89)90917-6.CrossRefPubMed
14.
Overgaard J, Hansen HS, Overgaard M, Bastholt L, Berthelsen A, Specht L, Lindelov B, Jorgensen K: A randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA) Protocol 5–85. Radiother Oncol. 1998, 46 (2): 135-146. 10.1016/S0167-8140(97)00220-X.CrossRefPubMed
15.
Oya N, Shibamoto Y, Sasai K, Shibata T, Murata R, Takagi T, Iwai H, Suzuki T, Abe M: Optical isomers of a new 2-nitroimidazole nucleoside analog (PR-350 series): radiosensitization efficiency and toxicity. Int J Radiat Oncol Biol Phys. 1995, 33 (1): 119-127. 10.1016/0360-3016(95)00040-6.CrossRefPubMed
16.
Kuwabara M, Iida Y, Inanami O, Sawamura S, Yokoyama K, Tsujitani M: Radiation-chemical properties of the hypoxic cell radiosensitizer doranidazole (PR-350). J Radiat Res (Tokyo). 2002, 43 (1): 77-88. 10.1269/jrr.43.77.CrossRef
17.
Aoki M, Furusawa Y, Shibamoto Y, Kobayashi A, Tsujitani M: Effect of a hypoxic cell sensitizer doranidazole on the radiation-induced apoptosis of mouse L5178Y lymphoma cells. J Radiat Res (Tokyo). 2002, 43 (2): 161-166. 10.1269/jrr.43.161.CrossRef
18.
Hamasu T, Inanami O, Tsujitani M, Yokoyama K, Takahashi E, Kashiwakura I, Kuwabara M: Post-irradiation hypoxic incubation of X-irradiated MOLT-4 cells reduces apoptotic cell death by changing the intracellular redox state and modulating SAPK/JNK pathways. Apoptosis. 2005, 10 (3): 557-567. 10.1007/s10495-005-1888-x.CrossRefPubMed
19.
Shibamoto Y, Kubota T, Kishii K, Tsujitani M: Radiosensitivity of human pancreatic cancer cells in vitro and in vivo, and the effect of a new hypoxic cell sensitizer, doranidazole. Radiother Oncol. 2000, 56 (2): 265-270. 10.1016/S0167-8140(00)00181-X.CrossRefPubMed
20.
Murata R, Tsujitani M, Horsman MR: Enhanced local tumour control after single or fractionated radiation treatment using the hypoxic cell radiosensitizer doranidazole. Radiother Oncol. 2008, 87 (3): 331-338. 10.1016/j.radonc.2008.03.002.CrossRefPubMed
21.
Yahiro T, Masui S, Kubota N, Yamada K, Kobayashi A, Kishii K: Effects of hypoxic cell radiosensitizer doranidazole (PR-350) on the radioresponse of murine and human tumor cells in vitro and in vivo. J Radiat Res (Tokyo). 2005, 46 (3): 363-372. 10.1269/jrr.46.363.CrossRef
22.
Sunamura M, Karasawa K, Okamoto A, Ogata Y, Nemoto K, Hosotani R, Nishimura Y, Matsui K, Matsuno S: Phase III trial of radiosensitizer PR-350 combined with intraoperative radiotherapy for the treatment of locally advanced pancreatic cancer. Pancreas. 2004, 28 (3): 330-334. 10.1097/00006676-200404000-00023.CrossRefPubMed
23.
Deeken JF, Loscher W: The blood–brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res. 2007, 13 (6): 1663-1674. 10.1158/1078-0432.CCR-06-2854.CrossRefPubMed
24.
Schneider SW, Ludwig T, Tatenhorst L, Braune S, Oberleithner H, Senner V, Paulus W: Glioblastoma cells release factors that disrupt blood–brain barrier features. Acta Neuropathol. 2004, 107 (3): 272-276. 10.1007/s00401-003-0810-2.CrossRefPubMed
25.
Towner RA, Smith N, Doblas S, Garteiser P, Watanabe Y, He T, Saunders D, Herlea O, Silasi-Mansat R, Lupu F: In vivo detection of inducible nitric oxide synthase in rodent gliomas. Free Radic Biol Med. 2010, 48 (5): 691-703. 10.1016/j.freeradbiomed.2009.12.012.CrossRefPubMed
26.
Asanuma T, Doblas S, Tesiram YA, Saunders D, Cranford R, Yasui H, Inanami O, Smith N, Floyd RA, Kotake Y: Visualization of the protective ability of a free radical trapping compound against rat C6 and F98 gliomas with diffusion tensor fiber tractography. J Magn Reson Imaging. 2008, 28 (3): 574-587. 10.1002/jmri.21474.CrossRefPubMed
27.
Liu R, Wen Y, Perez E, Wang X, Day AL, Simpkins JW, Yang SH: 17beta-Estradiol attenuates blood–brain barrier disruption induced by cerebral ischemia-reperfusion injury in female rats. Brain Res. 2005, 1060 (1–2): 55-61.CrossRefPubMed
28.
Schwartz DL, Powis G, Thitai-Kumar A, He Y, Bankson J, Williams R, Lemos R, Oh J, Volgin A, Soghomonyan S: The selective hypoxia inducible factor-1 inhibitor PX-478 provides in vivo radiosensitization through tumor stromal effects. Mol Cancer Ther. 2009, 8 (4): 947-958. 10.1158/1535-7163.MCT-08-0981.CrossRefPubMedPubMedCentral
29.
Rapoport SI: Osmotic opening of the blood–brain barrier: principles, mechanism, and therapeutic applications. Cell Mol Neurobiol. 2000, 20 (2): 217-230. 10.1023/A:1007049806660.CrossRefPubMed
30.
Weinmann M, Welz S, Bamberg M: Hypoxic radiosensitizers and hypoxic cytotoxins in radiation oncology. Curr Med Chem Anticancer Agents. 2003, 3 (5): 364-374. 10.2174/1568011033482350.CrossRefPubMed
31.
Ludemann L, Grieger W, Wurm R, Wust P, Zimmer C: Quantitative measurement of leakage volume and permeability in gliomas, meningiomas and brain metastases with dynamic contrast-enhanced MRI. Magn Reson Imaging. 2005, 23 (8): 833-841. 10.1016/j.mri.2005.06.007.CrossRefPubMed
32.
Matsumoto S, Yasui H, Batra S, Kinoshita Y, Bernardo M, Munasinghe JP, Utsumi H, Choudhuri R, Devasahayam N, Subramanian S: Simultaneous imaging of tumor oxygenation and microvascular permeability using Overhauser enhanced MRI. Proc Natl Acad Sci USA. 2009, 106 (42): 17898-17903. 10.1073/pnas.0908447106.CrossRefPubMedPubMedCentral
33.
Yasui H, Matsumoto S, Devasahayam N, Munasinghe JP, Choudhuri R, Saito K, Subramanian S, Mitchell JB, Krishna MC: Low-field magnetic resonance imaging to visualize chronic and cycling hypoxia in tumor-bearing mice. Cancer Res. 2010, 70 (16): 6427-6436. 10.1158/0008-5472.CAN-10-1350.CrossRefPubMedPubMedCentral
Metadata
Title
The prospective application of a hypoxic radiosensitizer, doranidazole to rat intracranial glioblastoma with blood brain barrier disruption
Publication date
01-12-2013
Published in
BMC Cancer / Issue 1/2013
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-13-106

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