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Grant enhances study of new chemotherapy targets

Oct. 18, 2018, 9:05 AM

by Tom Wilemon

Vanderbilt chemists have been awarded $7.2 million over the next five years from the National Cancer Institute to lead an initiative to better understand how a combination chemotherapy for breast cancer targets DNA.

Michael Stone, PhD, Carmelo Rizzo, PhD, and Martin Egli, PhD, will research the chemical biology of guanine alkylation that occurs with cyclophosphamide and doxorubicin, a treatment often referred to as AC chemotherapy regimen. The chemotherapies are mainstay treatments that have been in clinical use for decades, and there are well-established ideas of how they damage DNA of cancer cells. However, side effects can limit their effectiveness.

“It’s thought that cyclophosphamide and doxorubicin act on different targets independently, but we suspected that they can act synergistically,” said Rizzo, professor of Chemistry and Biochemistry and a researcher with Vanderbilt-Ingram Cancer Center (VICC). “We were able to come up with initial chemical evidence for this idea. The grant is based on this. If they do act synergistically, this could lead to new drugs designed to take advantage of this new mechanism.”

At this point, the research initiative is directed at basic science and does not include clinical trials, but better understanding how AC chemotherapy regimen interacts with DNA could ultimately lead to adjustments in dosages and the order by which the individual drugs are given that could lessen the potential for long-term harmful side effects.

“One of the ways that doxorubicin interacts with DNA is that it slips between base pairs, sort of like a penny between a roll of quarters,” said Egli, a professor of Biochemistry and VICC researcher. “The assumption was that the glycone, which is the sugar part of the doxorubicin drug, interacts with base pairs from the major groove side in a non-covalent fashion. However, endogenous formaldehyde abundantly present in our bodies might result in a covalent interaction between DNA and doxorubicin that would fundamentally alter how the drug interferes with information transfer and proteins that bind to and/or process DNA.”

Doxorubicin has also been shown to interfere with topoisomerases, enzymes involved in cell division.

“Now, it’s generally thought that the mechanism of action of doxorubicin in these chemotherapeutic regimens involves disruption of cell division by interfering with topoisomerases,” said Stone, professor of Chemistry and VICC researcher. “With our proposal, we have kind of gone full circle and said, ‘Wait a minute, maybe we need to go back to the interactions with DNA.’”

Research partners on the grant include Robert Turesky, PhD, of the University of Minnesota and Stephen Lloyd, PhD, and Amanda McCullough, PhD, both of Oregon Health and Science University.

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