BioWorld International Correspondent

LONDON - A method of protecting blood cells from the toxic side effects of radiation could one day help to safeguard patients having novel targeted radiation treatments for cancer.

Studies in the UK have shown that providing blood cells with an extra copy of a gene that encodes a protective enzyme can help the cells to survive doses of radiation that normally would be lethal.

If the work can be successfully translated into the clinic, it would allow patients to receive higher doses of radiation therapy with fewer side effects.

Thomas Southgate, postdoctoral fellow at the Cancer Research UK Gene Therapy Group at the Paterson Institute for Cancer Research in Manchester, UK, told BioWorld International: "Our study provides proof of principle that it is possible to avoid the dose-limiting effects of ionizing radiation.

"The work is a long way from the clinic at the moment, but the signs for the future are very promising," he said.

Southgate and his colleagues, who carried out the work in the laboratory of the late Leslie Fairbairn, report their findings in a paper in the Feb. 28 issue of The Journal of Gene Medicine. Its title: "Radioprotective Gene Therapy Through Retroviral Expression of Manganese Superoxide Dismutase."

Some of the new treatments scientists are trying to develop to treat cancer rely on coupling a radioisotope to an antibody. Such combination therapies are known as radioimmunotherapeutics. The antibody binds to antigens found only on the patient’s cancer cells, bringing the radiation source into close proximity with them. The cancer cells, which are dividing rapidly, will die as a result.

Unfortunately, normal cells that divide rapidly also succumb to radiation.

The result is the classically observed side effects of traditional cancer radiotherapy - such as loss of hair, sickness and anemia - which are all due to the loss of rapidly dividing cells in the hair follicles, gut and bone marrow, respectively.

Although radioimmunotherapeutics are much more highly targeted than traditional radiotherapy, the blood and bone marrow remain at high risk because radioimmunotherapeutics are delivered by injection into the blood stream.

Fairbairn, Southgate and their colleagues decided to try to develop a way to reduce the harmful side effects of radioimmunotherapeutics on the bone marrow.

They knew that radiation mainly damages cells in two ways: There is direct damage to the DNA, and indirect damage resulting from the cell’s production of free radicals known as reactive oxygen species. The latter are unstable, and can cause reactions that result in damage to DNA and, ultimately, cell death.

Cells have evolved enzymes called superoxide dismutases to help them deal with such events. One of these, called SOD2, is found almost exclusively in the mitochondria. SOD2 rapidly converts reactive oxygen species into hydrogen peroxide. That, in turn, can be metabolized by the enzyme catalase.

Previous studies by other groups had shown that overexpression of SOD2 could protect cells from the effects of ionizing radiation. The Manchester group decided to investigate whether they could achieve the same results with haematopoietic stem cells. They used a retrovirus to insert the gene encoding SOD2 into the DNA of cells from a human leukemia cell line, and into that of cells from the bone marrow of mice.

The genetic material that was inserted was flanked by DNA, which ensured the SOD2 gene would be powerfully expressed in blood cells.

After bombarding the genetically manipulated cells with radiation, they found that cells with an extra copy of SOD2 were able to carry on proliferating at doses of radiation that would normally kill unprotected cells, proving that the extra gene gave them significant protection from the effects of radiation.

Southgate said: "The next question is whether it will be clinically effective. The answer is probably no, at this stage, because we do not believe that there is enough radioprotection occurring. Our current work is moving toward trying to improve the efficacy of this radioprotection."

One strategy, which the team already has begun to evaluate, is to add in the gene for catalase into the cassette of genes that the retrovirus delivers to the cells.

Southgate said: "SOD2 turns the reactive oxygen into hydrogen peroxide, and the cell needs to get rid of this. We think the buildup of hydrogen peroxide may be the step limiting the amount of protection that the cell can get. Initial studies done with viruses that contain both SOD2 and catalase have been very encouraging. Our next step will then be to carry out in vivo studies."

No Comments