By David N. Leff

The name Chernobyl - like Hiroshima, Nagasaki and Three Mile Island - has become emblematic of misdirected atomic energy. On April 26, 1986, in what was then the Soviet Union, an accident at the Chernobyl Nuclear Power Plant's Unit 1 caused an immense release of ionizing radiation, and the permanent shutdown of the facility.

This catastrophe fired a global shot in the foot to public acceptance of nuclear power, and a shot in the thyroid for children trapped in Chernobyl's insidious spin-off.

Clinical molecular oncologist Yuri Nikiforov has studied this phenomenon for the past decade. "It's been well known for many years," he told BioWorld Today, "that radiation is a carcinogen. It leads to tumor development many years after exposure. Examples are leukemia, thyroid cancer and many other malignancies.

"After accidental exposure," he continued, "even after therapeutic radiation, patients remain at high risk of developing some kind of cancer for four to 40 years."

Nikiforov, now at the University of Cincinnati, Ohio, began his work while still a pathologist in what is now Belarus, just north of Chernobyl. He analyzed thyroid cancer tissues from 80 children who had acquired the disease from that radiation.

"Most of the contamination came from internal exposure," he recalled. "That means radioisotopes were ingested - swallowed - and deposited in various tissues of the children's bodies. Three major isotopes with biological significance at Chernobyl were radioactive iodine, strontium and cesium.

"Iodine has a very short-lived isotope," Nikiforov pointed out. "Its half-life is eight days. But after Chernobyl, because the population was not informed about the accident, they continued to drink milk from the surrounding farms. And the pathway was radioisotopes to the grass, from grass to the cow, from cow to the milk and from milk to the children."

Hazardous Effects Still Linger

"The present situation around Chernobyl," he went on, "is that radioiodine was gone from the environment a long time ago. Cesium and strontium are still present in the soil, and in some agricultural products, but they were deposited in bones and soft tissues. Nothing to do with thyroid."

Nikiforov explained that, "The thyroid gland is particularly sensitive to radiation because thyroid is the only organ in our body that specifically accumulates iodine. And that is why, when radioiodine is ingested, it preferably accumulates in thyroid tissue, not in any other. And that is why the Chernobyl children received very high doses of exposure, followed by development of papillary thyroid cancer."

Why children are the targets of choice for radiation, Nikiforov said, "is a very hot research topic no, because it's true that after all kinds of accidents, children are by far the most vulnerable population. We do not know why," he added, "but we are working on this question."

Nikiforov is senior author of a paper in today's issue of Science, dated Oct. 6, 2000. Its title: "Proximity of chromosomal loci that participate in radiation-induced rearrangements in human cells."

His research on the Chernobyl children, Nikiforov pointed out, "allowed us to come up with the hypothesis that we prove in this Science paper. Many types of cancer associated with radiation exposure," he explained, "have chromosomal rearrangements.

"For many decades, the questions were: Why in thyroid cancer do we have chromosomal fusion of the RET and H4 genes? Why in leukemias do we have the so-called Philadelphia chromosome fusion? Why two chromosomal regions very far from each other, consistently fuse together to make the rearrangement? And this paper gives an answer.

"We found that in normal human cells," Nikiforov recounted, "because of the chromosomal architecture, because chromosomes are spatially arranged to move in the nucleus, these two regions may be spatially adjacent - close to each other. Radiation produces breaks in DNA. And because these free ends are in close proximity, they are prone to misjoining, which leads to rearrangement.

"Initially, they were very far from each other, like the thyroid-specific RET and H4 genes, both on chromosome 10 - and 30 megabases apart. That's a huge distance, with many, many genes located between them. The question is why radiation makes them consistently fuse to each other.

"In normal thyroid cells," he went on, "these two pieces of DNA on chromosome 10 - the RET and H4 genes - came into very close contact, and stayed that way. This predisposed them to be damaged simultaneously by a single radiation beam. And that led to fusion, rearrangement and eventually papillary thyroid cancer."

Nikiforov drew a word picture of a chromosomal inversion - a typical rearrangement: "A chromosome," he suggested, "is like a long strand of spaghetti. And if you cut out one inch of this spaghetti, flip it over end to end, and reattach it in a wrong way, that is inversion. As for the cellular pathway from that rearrangement to tumorigenesis, it's not known at this moment. Again, a very hot area right now.

"There is no direct clinical application of our work to date," Nikiforov observed. "This is just a fundamental mechanism of how radiation may lead to chromosomal rearrangement and tumor development. In the long term, it may be of big significance - if we really prove that this proximity is a prerequisite for generation of chromosomal rearrangement.

Drug Therapy? Conceivable But Hypothetical

"Some drugs available right now," he pointed out, "mainly chemotherapeutic agents, can change chromosomal architecture. Take a situation where somebody needs to have his or her thyroid exposed to radiation for whatever reason. Maybe for treatment of another malignant disease. Conceptually," he theorized, "say there is Hodgkin's disease in both neck lymph nodes. The current standard of treatment exposes the entire area to external radiation. That's a situation where the thyroid needs protection against this exposure.

"So if we developed a drug that disrupts this proximity between the RET gene and another gene that we have rearranged, we can give it to the patient in advance - then expose him. In several hours, this compound, which has a reversible effect, will be eliminated, and the genes will come back together to normal. Potentially," Nikiforov concluded, "this phenomenon could help us develop therapeutic strategies aimed at protecting human cells from generating rearrangement, and eventually cancer."

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