A drug used for decades to treat leukemia may have other uses in the fight against cancer, researchers at the University of Missouri have found. Previously, doctors used 6-Thioguanine, also known as 6-TG, a synthetic guanosine analogue antimetabolite being used as a chemotherapy treatment to kill cancer cells in patients with leukemia.

Phosphorylated by hypoxanthine-guanine phosphoribosyltransferase, thioguanine incorporates into DNA and RNA, resulting in inhibition of DNA and RNA syntheses and cell death. This agent also inhibits glutamine-5-phosphoribosylpyrophosphate amidotransferase, thereby inhibiting purine synthesis.[1]

A second drug,Zebularinealso known as Zeb, a similar cytidine analog, also has demethylating activity as well as oral bioavailability

In recent years, many doctors have shelved 6-TG and Zeb in exchange for newer drugs that are more effective. Now, Jeffrey Bryan, an associate professor of oncology at the MU College of Veterinary Medicine, and his colleagues found that 6-TG and Zeb can not only kill cancer cells, but also works to change how certain cancer cells function, weakening those cells so they can be killed by other drugs.


We can use 6-TG to turn off dangerous markers in cancer cells so that those cells become easier to kill, we then can use more powerful cancer-killing drugs to eliminate the cells for good…

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Every cell in the body has certain genetic characteristics called epigenetic markers that give cells instructions on how to act, when to multiply and when to die. Cancer cells often have epigenetic markers that cause genes to be either turned off or out of control. This causes those cells to grow rapidly, become difficult to kill and ultimately damage the body. When testing the drug on cells from dogs with cancer, the MU researchers found that 6-TG can affect these epigenetic markers in cancer cells through a chemical process called demethylation. This process works to turn off damaging epigenetic markers and turn on markers that make the cells act in a healthy manner. Bryan says this discovery could lead to future cancer treatments using multiple drugs to fight the disease from different sides.

Turning off dangerous markers
?While 6-TG is no longer one of the more powerful cancer-killing drugs doctors have at their disposal, we found that it could still be useful to fight cancer in conjunction with other drugs,? Bryan said, who also is the director of the Comparative Oncology and Epigenetics Laboratory at MU. ?If we can use 6-TG to turn off dangerous markers in cancer cells so that those cells become easier to kill, we then can use more powerful cancer-killing drugs to eliminate the cells for good.?

Bryan says this research could potentially open doors for future research on other old cancer drugs that are no longer used by doctors. By re-examining other potential uses for these old drugs, Bryan says more effective treatments could be found. He also says that doing this research on dogs with cancer could translate well to human diseases.

Similar in dogs and humans
?Epigenetic markers work similarly in dogs and humans, so we expect to see similar results with these drugs in humans as we do in dogs,? Bryan said. ?This is ?a one step back, two steps forward? approach to cancer research. Gaining approval from the Federal Drug Administration (FDA) to use new drugs to treat human diseases is a difficult, time-intensive process. By examining alternate uses of old drugs in dogs, we hope to be able to expedite that process down the road when we introduce these novel combination treatments in humans.?

This study was first published in BMC Veterinary Research. Bryan?s co-authors include Senthil Kumar, an assistant research professor and assistant director of the Comparative Oncology and Epigenetics Laboratory at the MU College of Veterinary Medicine, and Brian Flesner, a former resident at the MU College of Veterinary Medicine and current faculty member at Louisiana State University.[2]

Human drug testing
The early-stage results of this research are promising, confirming the demethylating action of 6-TG and Zeb in canine cells, as well as confirming a similar demethylating mechanism as that shown in human cell lines. This supports the need forin vivoresearch to determine whether these compounds could improve response to therapy in dogs with resistant lymphoma. If these additional studies, including animal studies, are successful within the next few years, the researchers will request permission from the federal government to begin human drug testing. After this status has been granted, Bryan and his colleagues may conduct human clinical trials in conjunction with oncologists at the MU Ellis Fischel Cancer Center with the hope of developing new treatments.

For more information:
[1] National Cancer Institute. NCI Directory of Cancer Drugs.
[2]Flesner BK, Kumar SR, Bryan JN. 6-Thioguanine and zebularine down-regulate DNMT1 and globally demethylate canine malignant lymphoid cells. BMC Veterinary Research Volume 10

Photo: Jeffrey Bryan, an associate professor of oncology at the MU College of Veterinary Medicine and director of Comparative Oncology and Epigenetics Laboratory, found that 6-Thioguanine, or 6-TG, can not only kill cancer cells, but also works to change how certain cancer cells function in dogs with cancer. Photo Courtesy: University of Missouri.


Last Editorial Review: April 2, 2015

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