Web Date: March 14, 2012
Nucleoside Pulls Double Duty In Anticancer Treatment
Acute lymphoblastic leukemia is the most common type of childhood leukemia, with about 5,000 children diagnosed in the U.S. each year. Now researchers have synthesized a nonnatural deoxynucleoside that could selectively kill leukemia cells by gumming up their DNA replication (ACS Chem. Biol., DOI: 10.1021/cb300038f). The compound also provides a chemical handle to help scientists and doctors monitor the drug’s incorporation into cells.
Blocking DNA replication is a common research strategy for attacking acute lymphoblastic leukemia (ALL). About 90% of these leukemia cells overexpress a unique type of DNA polymerase that elongates single strands of DNA after the double strand breaks. Researchers had found a molecule called cordycepin to block this enzyme; cordycepin is an analog of a nucleoside, which is a DNA or RNA base attached to a sugar. Unfortunately, polymerases that replicate chromosomal DNA also incorporate this molecule into their growing DNA strands, damaging healthy cells and causing side effects.
Anthony Berdis of Case Western Reserve University and his colleagues wanted to design an analog that would only block the repair enzyme overexpressed in ALL cells. The researchers started with a nonnatural deoxynucleoside that has a 5-nitroindole base, since they already knew it was selective: Repair polymerases, like the one ALL cells overexpress, incorporate it into a growing DNA strand more efficiently than polymerases that replicate chromosomal DNA do.
Next the chemists added an alkyne group to the 5-nitroindole base and found that the overexpressed polymerase bound the resulting deoxynucleoside, 3-ethynyl-5-nitro-2’-deoxynucleoside, 10 times more strongly than it bound 2’-deoxyadenosine. The polymerase also couldn’t extend a DNA strand that ended with the deoxynucleoside analog. The molecule disrupts the extension process, Berdis says, because it prevents the formation of a DNA double strand after the single strand extension.
The scientists tested the compound’s effectiveness at killing cancer cells by adding it to six lines of human leukemia cells, each with a different expression level of the repair polymerase. The researchers found that the toxicity of the deoxynucleoside analog increased with expression levels: The potency of the drug doubled as the enzyme level doubled.
The compound’s alkyne group also allowed the researchers to attach a fluorescent azide-containing dye to the drug and monitor how much it was incorporated into cellular DNA. Using flow cytometry, they found that as the dose of the nucleoside analog increased, so did the amount of fluorescent DNA inside cells. Berdis says that doctors could easily adapt this methodology into a blood test that would measure the amount of drug that made it into the DNA of a patient’s cancer cells. Such a test would allow a doctor to determine within days whether a drug dose worked, rather than waiting for weeks or months for the patient’s cancer cell numbers to drop.
“I think this work will create a new paradigm in personalized treatments against cancer,” he adds.
Biochemist Zucai Suo of Ohio State University says that adding the alkyne group to the inhibitor was smart because it adds diagnostic power to a potentially therapeutic molecule. But he points out that, before the compound can become a promising drug lead, the researchers still need to collect data on the nucleoside’s metabolic fate and on its affinity for other human DNA polymerases.
Berdis agrees and says such tests are under way.
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