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

Abstract

BackgroundGlioblastoma 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).MethodsReproductive 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.ResultsDoranidazole 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.ConclusionsOur 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.

Repositioning disulfiram as a radiosensitizer against atypical teratoid/rhabdoid tumor

“…36 Most importantly, many agents have focused on re-oxygenating hypoxic tumor tissues using several action mechanisms such as hypoxic cytotoxicity and the enhancement of oxygen diffusion. 37,38 Others inhibit key enzymes of DNA damage repair signaling (ie, ATM, ATR, CHK1, CHK2, and PARP) or cell survival signaling (ie, epidermal growth factor receptor, [ 11 C] methyl-L-methionine, phosphatidylinositol-3 kinase/Akt, and mammalian target of rapamycin). [39][40][41] Along with those targeted agents, nonspecific cytotoxic chemotherapeutic agents, including temozolomide, have been tested.…”

Radioresistance of Brain Tumors

“…Another important problem recognized for decades in radiobiological research, is that of intratumoral hypoxia and its role in radioresistance [ 123 , 124 , 125 ]. Strategies including the use of hyperbaric oxygen to improve oxygen supply to tumors or drugs that specifically target and radiosensitize hypoxic tumor cells have been exhaustively pursued [ 123 , 126 , 127 , 128 ]. However, it is evident from Jens Overgaard’s 2007 meta-analysis of 82 hypoxic radiosensitization clinical trials that the majority of trials evaluating CNS tumors treated with nitroimidazole-derived compounds as potentially useful radiosensitizers failed to show any clinical benefit [ 129 ].…”

The Role of Hypoxia and SRC Tyrosine Kinase in Glioblastoma Invasiveness and Radioresistance

“…Therefore, EPO receptor silencing not only increases the sensitivity of glioma cells to chemotherapy (temozolomide) as well as X-rays, but also counteracts the hypoxia-induced chemo- and radio-resistance [ 101 ]; for this reason, targeted therapy, such as specific antibodies, may be applied directly to EPO, EPO receptor, or to another downstream mediator of EPO receptor signaling pathway such as STAT3. Likewise, the hypoxic cell radiosensitizer doranidazole (PR-350) administration in malignant significantly enhanced radiation-induced reproductive cell death in vitro under hypoxia, suggesting a potent strategy for improving the clinical outcome of radiotherapy, reducing related side effects [ 102 ]. A promising strategy to enhance the radiosensitivity of GBM is represented by the application of targeted molecules that weaken the DNA damage response (DDR) signaling pathway.…”