Suppressing cancer cells' ability to replicate damaged DNA could dramatically enhance the effectiveness of chemotherapy drugs such as cisplatin, according to a new pair of papers from MIT biologists.
In studies of mice, the researchers found that slowing down a specific system for tolerating DNA damage not only prolonged survival but also prevented relapsed tumors from becoming resistant to chemotherapy, and made tumors much less likely to spread to other parts of the body.
Two enzymes that play key roles in a cell's response to DNA damage could be an enticing target for new cancer drugs, according to Michael Hemann and Graham Walker, senior authors of the two papers. Their new findings will appear in the Proceedings of the National Academy of Sciences.
Many cancer drugs, including cisplatin, kill cancer cells by damaging their DNA. This damage can impair a cell's ability to copy its DNA before cell division, resulting in cell death. However, cancer cells use enzymes known as translesion DNA polymerases to copy over damaged DNA and prevent the newly replicated DNA from having gaps in its normal sequence of nucleotide bases (the "rungs" of the ladder that forms the DNA double helix).
In these studies, the MIT researchers focused on two proteins, known as Rev3 and Rev1, which are subunits of translesion DNA polymerases.
In one of the PNAS papers, Hemann and Walker studied mice with a particularly aggressive form of lung cancer. Among mice treated with cisplatin, mice whose Rev3 levels were reduced by 60 to 70 percent lived twice as long as mice with the normal amount of Rev3. (Mice with reduced Rev3 lived an average of 22.5 days following cisplatin treatment; mice treated with cisplatin alone lived 11 days.) This is the first alteration shown to sensitize these tumors to front-line chemotherapy.
Translesion polymerases can be highly error-prone and thus introduce mutations into DNA. This can lead to drug-resistant tumors. Consistent with this idea, the researchers showed in a companion study that lymphomas with reduced Rev1 levels did not become resistant to chemotherapy following treatment and were much less aggressive in spreading to other parts of the body.
In that study, the researchers treated mice with the drug cyclophosphamide. At first, the drug was effective in mice whose tumors had normal and reduced Rev1, but in both groups, tumors reappeared after about two weeks. This is similar to the relapse that frequently occurs during the treatment of many human cancers.
Those relapsed tumors were then transplanted into a second group of mice. In the second group, drug treatment was strikingly more effective in mice with reduced Rev1. Those mice survived much longer -- 100 percent of the mice with reduced Rev1 lived for 12 days, whereas some of the mice with normal Rev1 level tumors died in two days and only 40 percent lived for 12 days. These experiments showed that reducing Rev1 levels prevented the tumor cells from acquiring drug resistance and aggressiveness when they relapse so that they can be successfully treated again.
The researchers' discoveries suggest that by inhibiting translesion DNA polymerases, it might be possible to treat difficult cancers that have proven resistant to ordinary chemotherapeutic treatments and also prevent the introduction of new mutations during chemotherapy.
In these studies, the researchers used a technique called RNA interference to block the expression of the genes that code for Rev3 and Rev1, but they were unable to shut off the genes completely.
Walker, an American Cancer Society Research Professor of Biology at MIT, is now looking for drugs that would disrupt the action of these polymerase enzymes. Such drugs might be able to shut down the translesion DNA polymerase system even more effectively than the RNA-interference approach used in these studies and could help to improve the effectiveness of chemotherapy.
Funding was provided by the National Institutes of Health, National Institute of Environmental Health Sciences, and MIT's Center of Environmental Health Sciences.
- Jason Doles, Trudy G. Oliver, Eleanor R. Cameron, Gerald Hsu, Tyler Jacks, Graham C. Walker, and Michael T. Hemann. REV3 supression sensitizes drug resistnat lung tumors to chemotherapy. Proceedings of the National Academy of Sciences, 2010; (in press)
- Kun Xiea, Jason Doles, Michael T. Hemann, and Graham C. Walker. Error-Prone translesion snythesis mediates acquired chemoresistance. Proceedings of the National Academy of Sciences, 2010; (in press)
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