Mechanism that triggers resistance to radiation after exposure
8 September 2011
University of Oslo researchers have discovered how exposure to
radiation can make cancer cells and normal cells resistant to
radiotherapy and chemotherapy.
Although radiation treatment is becoming increasingly important
in combating cancer, it can, due to resistance, work poorly for many
patients. "We don't know which patients are affected before
radiation treatment starts. This is a problem, especially when we
give curative cancer treatment," says Anne Hansen Ree, who is both a
professor of medicine at the University of Oslo and a chief
physician at Akershus University Hospital.
Two biophysicists, Professor Erik Olai Pettersen and Postdoctoral
Fellow Nina Jeppesen Edin of the Department of Physics at the
University of Oslo, have now discovered how it is possible to turn
the body's own resistance to radio- and chemotherapy on and off.
"This is new knowledge that opens possibilities for better
treatment. But there is a lot of research work ahead, so we don't
dare say which cancers the discovery might help fight," says
Pettersen, coordinator of the international cancer research project
Metoxia, which has received NOK100 million in EU support in recent
How resistance spreads.
Both high natural background radiation from rocks and medical
radiation treatment can lead to resistance to radiotherapy and
certain types of chemotherapy. When a patient is given radiation
treatments, some of the radiation unfortunately also hits healthy
tissue surrounding the tumour. In some cases, the healthy cells emit
resistance material. This is particularly unfortunate for patients
whose cancer is spreading.
"As resistance spreads to other tumours in the body, these
tumours also become immune to radio- and chemotherapy."
Pettersen points out that there are different resistance levels
to radiation and chemotherapy. The most studied is called multi-drug
resistance, where cancer cells pump the chemo out of themselves.
The two researchers have uncovered a completely different
mechanism. They have found the solution to how they can chemically
turn possible resistance to so-called low-dose rate radiation, where
radiation is given slowly over time, on and off.
As early as the nineties, researchers discovered that relatively
small doses of radiation can kill more cancer cells than slightly
larger doses of radiation. The two researchers have discovered that
if you are first exposed to a small radiation dose and then
subsequently receive a higher radiation dose, the effect of the last
dose is reduced because in the meantime, the cancer cells have
become resistant to radiation.
Jeppesen Edin irradiated cells with low-dose rate radiation.
Despite the fact that the cells divided four times a week, her
trials show that the descendants of the cells remained resistant to
radiation, five years after radiation. The cells were placed in a
liquid with nutrients. After irradiation Jeppesen Edin moved the
liquid containing the irradiated cells over to other unirradiated
cells, which also became resistant.
"This means that when we are exposed to a little radiation,
signal molecules are sent to our entire body via the circulatory
system. The cells that are not irradiated also become resistant
then," says Jeppesen Edin.
In other words, she found the signal molecule that can turn
sensitivity to radiation and toxins such as chemotherapy on and off.
The researchers have already found the signal molecule in the
blood of irradiated mice. "If we can detect this signal molecule in
the blood, we can see if the resistance is on or off in a patient."
Jeppesen Edin has shown that it is possible to turn off
resistance with an existing drug. "The drug has previously been
given to patients in a different connection with no reports of any
side effects. The drug does not damage the genetic material in the
cells, and attacks only the enzyme in the cell."
The idea is to give the patient an injection before radiation
treatment to make the cells hyper-sensitive again. "A single dose is
probably enough, but it is too early to say anything about this
today. We haven't yet tested its use on either animals or humans."
Sometimes it may be advisable to switch on resistance.
"Astronauts need extra protection from cosmic radiation. The same is
true of rescuers who have to enter radioactive areas, such as around
the earthquake-damaged Fukushima reactor in Japan. We are now
investigating whether the drug can also reduce the damage after one
has been exposed to radiation."
Some medical examinations have unfortunate consequences for
resistance to radiation. "Some lengthy CT examinations lead to so
much radiation that resistance can be turned on. However, the
radiation level in a standard X-ray examination is so low that
resistance is not turned on," says Pettersen.
Lessons learned from background radiation
The researchers discovered resistance while researching natural
background radiation. In Norway, background radiation varies locally
by a factor of ten. An area in Ramsar in the northern part of Iran
has one of the highest natural background radiations in the world.
Here, people can be exposed to background radiation a hundred times
higher than in Norway.
"Nevertheless, cancer rates are not higher in Ramsar than in
Norway. On the contrary, it is believed that the immune system takes
care of this. Resistance is therefore the body's natural protection
against elevated background radiation," says Pettersen the research
magazine Apollon, University of Oslo, Norway.
The research team has now applied for two patents via Inven2, the
University of Oslo's and South-Eastern Norway Regional Health
Authority's innovation company.
One patent deals with how resistance is measured in the blood.
The second patent concerns the use of a known substance, which can
turn off resistance. Inven2 believes the invention is not yet ready
"Inven2 clearly sees that this is advanced and exciting research,
but we do not yet know what proportion of those patients who respond
poorly to treatment have been subjected to low-dose radiation.
Moreover, we don't own the rights to the drug or similar substances
that can turn resistance off," says Jan Solberg, technology manager
at Inven2. He recommends that the research group find a completely
new substance that can be patented.