Pharmacological concentrations of ascorbate radiosensitize glioblastoma multiforme primary cells by oxidative DNA damage...

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mbstargrove@med...
Pharmacological concentrations of ascorbate radiosensitize glioblastoma multiforme primary cells by oxidative DNA damage...

 

Herst PM, Broadley KW, Harper JL, McConnell MJ. Pharmacological concentrations of ascorbate radiosensitize glioblastoma multiforme primary cells by increasing oxidative DNA damage and inhibiting G2/M arrest. Free Radic Biol Med 2012 Feb 2. [Epub ahead of print]

 

PMID: 22342518 
doi 10.1016/j.freeradbiomed.2012.01.021 
 
 
 
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Free Radic Biol Med. 2012 Feb 2. [Epub ahead of print]
 
Pharmacological concentrations of ascorbate radiosensitize glioblastoma multiforme primary cells by increasing oxidative DNA damage and inhibiting G2/M arrest.
 
Herst PMBroadley KWHarper JLMcConnell MJ.
Source
Malaghan Institute of Medical Research, Wellington 6242, New Zealand; Department of Radiation Therapy, University of Otago, Wellington 6242, New Zealand.
 
Abstract
Glioblastoma multiforme (GBM) has a very poor prognosis because of its chemo- and radiation therapy resistance. Here we investigated the ability of pharmacological concentrations of ascorbate to radiosensitize primary cells isolated from six GBM patients, mouse astrocytoma cells, and mouse astrocytes. We measured cell viability by trypan blue exclusion, generation of double-stranded DNA breaks by H2AX phosphorylation using fluorescently labeled antibodies and FACS analysis, apoptosis by annexin V/propidium iodide staining, inhibition of autophagy by 3-methyladenine, and cell cycle progression by propidium iodide staining of permeabilized cells. We showed that 5mM ascorbate in combination with 6Gy radiation killed more GBM primary cells by generating significantly more double-stranded breaks than either treatment alone (p<0.05). Combined treatment affected viability and double-stranded break generation in normal astrocytes to a much smaller extent. Radiation, but not 5mM ascorbate, caused G2/M arrest in GBM cells and ascorbate prevented radiation-induced G2/M arrest in combined treatment. Cell death in response to 5mM ascorbate or combination treatment was not mediated by apoptosis or autophagy. In conclusion, pharmacological concentrations of ascorbate radiosensitize GBM primary cells to a much greater extent than astrocytes; this large therapeutic ratio may be of clinical significance in radiation-resistant cancers.
 
Copyright  © 2012 Elsevier Inc. All rights reserved.
PMID: 22342518 
mbstargrove@med...
Vitamin C may enhance radiation tx for aggressive brain tumors

http://www.healthcanal.com/cancers/26731-Vitamin-may-enhance-radiation-t...
 Vitamin C may enhance radiation therapy for aggressive brain tumours16/02/2012 20:29:00 Recent research by the University of Otago, Wellington has shown that giving brain cancer cells high dose vitamin C makes them much more susceptible to radiation therapy.The study, carried out in association with Wellington’s Malaghan Institute was recently published in Free Radical Biology and Medicine.Lead author Dr Patries Herst together with Dr Melanie McConnell investigated how combining high dose vitamin C with radiation affected survival of cancer cells isolated from glioblastoma multiforme (GBM) brain tumours, and compared this with the survival of normal cells.They found that high dose vitamin C by itself caused DNA damage and cell death which was much more pronounced when high dose vitamin C was given just prior to radiation.Herst says GBM patients have a poor prognosis because the aggressive GBM tumours are very resistant to radiation therapy. “We found that high dose vitamin C makes it easier to kill these GBM cells by radiation therapy”.She says there has long been debate about the use of high dose vitamin C in the treatment of cancer. High dose vitamin C specifically kills a range of cancer cells in the laboratory and in animal models. It produces aggressive free radicals in the tumour environment but not in the environment of healthy cells. The free radicals damage DNA, which kills the cells, but the high concentration necessary to kill cancer cells can only be achieved by intravenous injection.However, these promising findings have so far not been validated in clinical studies. “If carefully designed clinical trials show that combining high dose vitamin C with radiation therapy improves patient survival, there may be merit in combining both treatments for radiation-resistant cancers, such as glioblastoma multiforme,” says Dr Herst.This study was funded by the Wallace Family Estate, Genesis Oncology Trust and a University of Otago Research Grant. For further information, contactDr Patries HerstDepartment of Radiation TherapyUniversity of Otago, WellingtonTel 64 4 383 8049

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