Measuring levels of DNA-repair enzymes before Chemotherapy could help minimize the cell damage

· TGI - Biomarkers, TGI - Cancer
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New research from Massachusetts Institute of Technology (MIT) may allow scientists to develop a test that can predict the severity of side effects of some common chemotherapy agents in individual patients. The new paper, which appears in PLoS Genetics, reveals that the amount of cellular damage that alkylating agents produce in healthy tissues can depend on how much of a certain DNA-repair enzyme is present in those cells. Levels of this enzyme, known as Aag, vary widely among different tissues within an individual, and among different individuals.

In this work, the researchers studied mice engineered to produce varying levels of Aag over a 10- to 15-fold range. This is similar to the natural range found in the human population. The mice with increased levels of Aag resembled normal mice in their lifespan and likelihood of developing cancer, says Jennifer Calvo, a research scientist in Samson’s lab and lead author of the paper. However, “we found drastic differences when we started challenging them with these alkylating agents,” she says.

Mice with excessive or even normal levels of the Aag enzyme showed much greater levels of cell death in certain tissues after being treated with alkylating agents. “It’s counterintuitive that extra DNA-repair capacity, or even the normal level, is bad for you,” says Samson, who is a professor of biological engineering and biology at MIT.

It appears that too much Aag can upset the balance in the base excision repair pathway, the researchers say. This pathway involves several steps, some of which produce intermediates that can be extremely toxic to the cell if they do not promptly move to the next step. The researchers theorize that when Aag is too active, these toxic intermediates build up and destroy the cell.  “It’s a very cell-specific phenomenon,” she says. “We haven’t completely gotten to the bottom of what it is that makes some cells behave in a certain way when they make zero or extra of a certain enzyme.”

 The researchers hope that if every thing is set and done, measuring levels of DNA-repair enzymes before chemotherapy may allow doctors to tailor treatments to minimize the damage.

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