Biophysicists discover how to turn body's own resistance to radiation treatment on and off

Radiation can make cancer cells resistant to radio- and chemotherapy. University of Oslo researchers have now figured out how resistance can be switched on and off.

By Yngve Vogt, research-magazine Apollon, University of Oslo

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 NOK 100 million in EU support in recent years.

How resistance spreads.

Both high natural background radiation, such as powerful 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.

Warning spread by the blood. Jeppesen Edin has been experimenting with cancer cells in a cell cultivation laboratory. The cells were irradiated 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 descendants retained the same resistance acquired by the original, irradiated cells."

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. "Surprisingly enough, these cells also became resistant."

Jeppesen Edin found the molecular explanation. The cancer cells that were irradiated emitted a signal molecule to the liquid. When the unirradiated cells came into contact with the liquid, they were told to turn on their resistance.

"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."

Medication.

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."

Astronauts.

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."

CT consequences.

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.

Patents.

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 for commercialization.

"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.