*Radiation Protectors*
1 Introduction
2 Oxygen enhancement ratio
3 Dose reduction factor
4 Amifostine
5 So what’s the problem? (And Summary)
Introduction
Some substances will confer an amount of protection from radiation.
One of the first radiation protectors discovered was cysteine. When given to mice it was found doses about 1.8 times higher than that of a control group were needed to give the same level of mortality. One of the problems with cyseine is its toxicity, as it produces nausea and vomiting if taken if the amounts required to provide any protection from radiation. Consequently, the US army started synthesizing large numbers of compounds at the Walter Reed army hospital (about 3,000 were tried) and one of the drugs developed was Amifostine. Amifostine is the inactive form of the compound, (activation is by dephosphorylation to the metabolite WR 1065 by the plasma membrane bound enzyme alkaline phosphatase). How does a chemical provide any radiation protection? And are they worth the trouble? To understand the effects we need to take a slight detour into the effect of oxygen on cells.
Oxygen Enhancement Ratio (OER)
Cells that contain different amounts of oxygen have different sensitivities to radiation. For human cells, the deficiency of oxygen protects the cells from radiation, and increasing the oxygen increases the cells sensitivity to radiation. Because of its effect, oxygen is referred to as a radio-sensitizer. A simple experiment can be carried out to illustrate the sensitivity of cells. This is to irradiate two groups of cells, one under normal conditions, and other under conditions of increased oxygen. The ratio of the dose required to kill the cells with the oxygen divided by the amount to kill cells without oxygen is referred to as the oxygen enhancement ratio (OER).
OER = (dose need to kill cells without oxygen) / (dose to kill cells without oxygen).
For example, suppose 50% of a group of cells were killed with 300 RAD and the dose needed to kill identical cells with some reduced level of oxygen was 600 RAD. The oxygen enhancement ratio would be 600/300 = 2. This does sound a bit backward, since removing the oxygen “enhances” the dose that can be applied, but if we think of the enhancement in the killing power of the radiation it makes sense. Add oxygen, enhance the killing power, hence an OER. Figure 1 shows a graph taken from [Hall 1994]. The maximum OER for human cells in a Petri dish is about 3, meaning the maximum difference in radiation doss for the same effect between full oxygen and zero oxygen conditions is a factor of 3.
Figure 1: An illustration of the oxygen enhancement ratio for
x-rays. Adding oxygen (denoted as aerated) to the cells makes them more
sensitive to the radiation, or enhances the radiation’s killing power, hence we
talk of an oxygen enhancement ratio. Shamelessly reproduced from [Hall 1994].
Dose Reduction Factor
From the above, if oxygen is removed from cells, the effect of radiation is reduced. The OER can be understood, at least a little bit, by understanding what happens when radiation interacts with material.
When x-rays or gamma rays interact in the body, they produce fast moving electrons which then create various reactive species, such as free radicals. From [Johns 1983] a few of the chemical reactions are shown. Once the free radicals are produced, they immediately begin interacting with the surrounding chemicals, one of which is DNA. Now DNA can be affected by direct photon ionization, or by the electrons produced by the ionizing radiation, but most of the interaction are from the free radicals.
Scavenging the free radicals with some other chemical, "mopping them up" before they can do more damage will reduce the effect of the radiation. Effectively, this is how the radiation protectors discussed here work. Because some of the electrons and gamma rays will hit the DNA anyway, there will be some damage, no matter how efficient the radiation protector was. Additionally, gamma rays are sparsely ionizing radiation. A gamma ray has a lot of penetration because it gives up its energy in relatively small amounts. Neutrons or other radiation, because they act like giant bowling balls smashing everything in there path tend to overload any scavenging of free radicals.
Consequently, we would not expect a radiation protector to have more effect than removing the oxygen altogether. The maximum protection for a perfect scavenger would be about three.
The dose reduction factor (DRF) is the dose for a given lethality with the drug divided by the dose for the same effect in the absence of the drug.
DRF = (dose for a given effect with protection) / (dose for the same effect)
for example if 600 RAD produced 50% cell kill with a certain drug, and 300 RAD produced the same cell death without the drug the DRF would be 2.
Figure 2: Some Free radical reactions caused by ionizing
radiation. Aqueous electrons very rapidly bind to oxygen and form various free
radicals and ions. Examples are from [Johns 1983]
Amifostine
Several different radiation protector drugs exist, here I will write mainly of amifostine since amifostine has a wide current medical use. Amifostine is a quite common radiation protector drug. Several years ago Amifostien was regularly used most lung cancer treatments during radiation therapy.
Amifostine scavenges free radicals produced by radiation and inactivates active species through formation of thioether conjugates. The scavenging of reactive oxygen species (ROS) has been noticed in TBI treatments [Facorro 2004]
Amifostine has been approved by the USA FDA as a radioprotector [FDA 1999]. Amifostine is also known as "Ethyol". Lunar astronauts were given the chemical for an emergency use.
Amifostine has been used to protect normal cell function during chemotherapy [Lurruso 2003] and during combined chemo-radiation therapy [Movsas 2005]
Amifostine is reported as being usually well tolerated, with the most clinically significant side effect (dose-limiting toxicity) being hypotension [Devita 1997]. Others would add that fevers, chills and sweating are common effects too. The subcutaneous method rather than IV tends to be more tolerated, for example [Kouk 2003].
As an example of clinical use, in China [Liu 1992] two groups of patients with rectal cancer were treated with radiation, one with and one without amifostine. With amifostine no rectal toxicities were seen, with out it, 14% of the patients had some rectal and bladder toxicity. Other results include reduction of pain in swallowing following treatment for lung cancer [Sarna 2008].
What is of interest here is not the medical uses for localized areas, but the effects of these radiation protectors for whole body irradiation. Total body irradiation is used for different therapies, such as leukemia and bone marrow transplant [Facorro 2004], Gabriel [2000]
The results of amifostine are detectable in large groups. In mice, the factor of protection from total body irradiation approaches three. The main clinical justification is that tumor vascularization is not as complete as normal tissue. This means that blood will carry the amifostine to the normal tissue, and that the amifostine will only diffuse slowly into the tumor. If amifostine is given a few minutes before some radiation therapy, the normal tissue will be protected, and the tumor will not be affected. Also, amifostine affords sparing to the gastrointestinal lining and the salivary glands quite well due to the hydrophilic nature of the drug, but doesn’t cross the blood-brain barrier to protect the brain.
So what’s the problem? (And Summary)
Well, radiation protection can be shown for mice, and for medical therapy. Since amifostine acts by scavenging the free radicals, it must be given before the radiation. It is of no use in radiation protection after the event. Amifostine and sulfhydryl groups will be broken down in the stomach, so a tablet isn’t going to help. This means a subcutaneous injection (usually the stomach) or an IV. The Soviet army use to carry Cystaphos, a similar sulfhydryl chemical to amifostine, but it was provided in tablet form. Useful? No. Unlike KI, which can be given to a general population as a tablet, a radiation protector will require a measured dose delivered by IV or subcutaneous injection.
Summary Points:
Decreasing the Oxygen concentration makes a cell more resistant to radiation
Radiation protectors can scavenge free radicals produced by radiation and protect cells
The maximum radiation protection would be a factor of three.
Radiation protectors have to be given before a radiation exposure
References and further reading
Offline
[Devita 1997] Devita et al, Cancer, principles and practice of oncology, page 3089, 5th edition Lippencott-Raven.
[Hall 1994] Hall, E. Radiobiology for the Radiologist 4th edition Lippencott and Williams 1994 ISBN 0-397-51248-1
[Johns 1983] Johns and Cunningham The Physics of Radiology 4th edition. Charles C. Thomas. ISBN 0-398-04669-7
[liu 1992] Liu T, Liu Y, He S et al.Use of radiation with or without amifostine in advanced rectal cancer. Cancer 1992; 69: 2820-2825
Online
[Hall 2006] Hall, E. Radiobiology for the Radiologist, 2006.
[Lorusso 2003] D. Lorusso et al, Phase III multicenter randomized trial of amifostineas cytoprotectant in first-line chemotherapy in ovarian cancer patients, Annals of Oncology 14:1086-1093, 2003
http://annonc.oxfordjournals.org/cgi/content/full/14/7/1086
[Movsas 2005] B. Movsas et al, Randomized trial of amifostine in locally advanced non-small-cell lung cancer patients receiving chemotherapy and hyperfractionated radiation: radiation therapy oncology group trial 98-01 J Clin Oncol 2005 April 1;23(10):2145-54.
http://www.ncbi.nlm.nih.gov/pubmed/15800308?dopt=Abstract
[Sarna 2008] L Sarna et al, Clinically Meaningful Differences in Patient-Reported Outcomes With Amifostine in Combination With Chemoradiation for Locally Advanced Non-Small-Cell Lung Cancer: An Analysis of RTOG 9801. Int J Radiat Oncol Biol Phys.2008 May 21.
http://www.ncbi.nlm.nih.gov/pubmed/18501528?dopt=Abstract
[Facorro 2004] G. Facorro et al, Oxidative study of patients with total body irradiation: effects of amifostine treatment Bone marrow transplantation 2004,vol.33,no8,pp.793-798
http://cat.inist.fr/?aModele=afficheN&cpsidt=15625225
[Gabriel 2000] D. Gabriel et al, Use of Amifostine to Reduce Mucositis Following Total Body Irradiation (Tbi)-Based Autotransplants for Lymphoma Proc Am Soc Clin Oncol 19: 2000 (abstr 268A)
[FDA 1999] FDA Amifostine datasheet
http://www.fda.gov/Cder/foi/label/1999/20221s12lbl.pdf
[Koukourakis 2003] Koukourakis M I, Amifostine before Chemotherapy Improved Tolerance Profile of the Subcutaneous Over the Intravenous Route Clinical Cancer Research Vol. 9, pages 3288-3293, August 2003
http://clincancerres.aacrjournals.org/cgi/content/full/9/9/3288
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