Researchers at Washington University School of Medicine in St. Louis have found that human cells have a way of detecting and mending DNA damage caused by some common chemotherapy drugs, and to knock out this mending function may increase the potency of certain chemotherapy drugs in treatment of cancer.
The findings have been newly published in the journal Nature.
Some of the oldest chemotherapy drugs are known as alkylating agents. They kill cancer cells by adding groups of carbon and hydrogen atoms to or alkylating DNA.
"We found that human cells can sense alkylation damage and mobilize a repair complex specifically suited to repair this kind of injury," said senior author Nima Mosammaparast, an assistant professor of pathology and immunology at Washington University School of Medicine.
Alkylation can happen naturally, which is why cells have this repair system in the first place. Certain chemotherapy drugs also force it to happen.
Studying cells treated with alkylating chemotherapy drugs or with drugs that lead to other kinds of DNA damage, the researchers have determined how cells try to mend DNA damage caused specifically by alkylating agents. They identified a group of proteins that clustered near the spots on the DNA that had been alkylated. When treated with alkylating drugs, cells lacking a key member of this protein complex were more likely to die than cells having the protein.
These findings suggest that sensing alkylation damage is a major primary defense against chemotherapy drugs and other alkylating agents. Interfering with this repair complex could amplify the killing power of such drugs and potentially even avert or undermine drug resistance.
Tumors that have high levels of key alkylation repair proteins are often dependent on them. If those proteins were somehow inhibited, the cells would die.
"That could be an opening for a chemotherapy drug," Mosammaparast said. "We may be able to design a drug that is toxic to tumors but not to normal cells by targeting this alkylation repair pathway."
