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Genetic Damage from Leukemia Drugs Persists among Children

By Cheryl Simon Silver

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Leukemia and Lymphoma

In the last decade, therapies used to treat children with acute lymphocytic leukemia (ALL) have improved the survival rates dramatically, but they also cause genetic mutations in the children. A new study reports that the treatments cause a high rate of mutations and says that the genetic damage persists in the children long after the cancer is in remission.

Researchers have known for several years that patients treated for ALL experience some mutations in both malignant and nonmalignant cells. A paper published this week in Cancer Research shows that the rate of genetic mutations increases rapidly over the course of treatment.

“Overall, the frequency of mutations increased 200 times and remained elevated for more than five years after treatment stopped,” says Barry A. Finette, a pediatrician and molecular biologist at the University of Vermont in Burlington who led the study. “This is a surprising observation.”

Yet the clinical effects of the mutations are unknown. “There is no evidence that these mutations lead directly to any abnormal health effects or disease,” Finette says.

But as scientists learn more about the mutations, they may be able to understand why children cured of ALL are five to twenty times more likely to develop other cancers and diseases later in life than are children who did not have the disease, says Finette.

With colleagues, Finette examined T cells in the blood of children treated with chemotherapy drugs to learn the frequency of mutations that occurred after treatment began.

All humans develop some genetic mutations with age, often in response to environmental toxins. In this case the “toxin” is the standard chemotherapy that doctors credit with the survival of more than 80 percent of children with ALL, which comprises four-fifths of acute childhood leukemia cases.

The researchers monitored 45 children. They examined blood samples from the children prior to their treatments and continued until at least five years after treatments ceased.

In general, genetic damage is associated with changes with cell properties, and it would help researchers to know if and how the changes are related to the development of later cancers or other diseases.

A study published this week in the New England Journal of Medicine shows that supplementing one standard ALL therapy with a heart-protective drug may reduce or avoid the heart damage which is a serious side-effect of treatment for childhood cancer.

The finding is encouraging, says Finette, because it raises the possibility that researchers will find that this drug—or other drugs—may mitigate side effects, such as genetic mutations, that could potentially cause problems for the children decades after treatment ends.

“Certain agents could be given to patients to reduce the toxic effects of chemotherapy on the heart, kidneys, and reproductive systems,” he says. “That would be the ultimate goal, because treatment would be safer, but still effective.”

See Related GNN Story: Heart Drug May Help Children Treated for Leukemia

Rice, S.C. et al. Genotoxicity of Therapeutic Intervention in Children with Acute Lymphocytic Leukemia. Cancer Research 64, 4464-4471 (July 1, 2004).
Finette B.A. et al. Emergence of Genetic Instability in Children Treated for Leukemia. Science 288, 514-517 (April 2000).

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