Treating the Cancer Treatment: an Investigation into a Chemotherapy drug’s Toxic Product

One of the most difficult hurdles in cancer treatment development is designing a drug that can distinguish between a person’s healthy cells and cancer cells. Cancerous cells take advantage of the body’s already present machinery and biochemical processes, so when we target these processes to kill cancer cells, normal, healthy cells are also destroyed directly or through downstream effects of the drug. The trick to cancer treatment then is to design a drug that kills cancer cells faster than it harms healthy cells. To this end, efforts are being made to understand the finer details that differentiate the anti-cancer effects of a drug from its harmful effects on the individual. This is where the research of Dan Breysse comes in.

Dan a third-year master’s student working with Dr. Gary Merrill in the department of Biochemistry and Biophysics. Dan’s research focuses on a common chemotherapy drug, doxorubicin. Doxorubicin has been researched and prescribed for about 40 years and has been used as a template over the years for many other new drug derivatives. This ubiquitous drug can treat many types of cancer but the amount that can be administered is limited by its toxic effect on the individual. Nicknamed “the red death,” doxorubicin is digested and ultimately converted to doxorubicinol, which in high doses can cause severe and fatal heart problems. However, hope lies in the knowledge that doxorubicinol generation is not related to the drug’s ability to kill cancer cells. These mechanisms appear to be separate, meaning that there is potential to prevent the heart problems, while keeping the anti-cancer process active.

Cancer cells replicate and build more cellular machinery at a much faster rate than the majority of healthy cells. Doxorubicin is more toxic to fast-replicating cancer cells because its mechanism involves attacking the cells at the DNA level. Dividing cells need to copy DNA, so this aspect of doxorubicin harms dividing cells faster than non-dividing cells. It is common for chemotherapy drugs to target processes more detrimental to rapidly dividing cells which is why hair loss is often associated with cancer treatment.

Separately, doxorubicin’s heart toxicity appears to be regulated at the protein level rather than at the DNA level. Doxorubicin is converted into doxorubicinol by an unknown enzyme or group of enzymes. Enzymes are specialized proteins in the cell that help speed up reactions, and if this enzyme is blocked, the reaction won’t occur. For example, an enzyme called “lactase” is used to break down the sugar lactose, found in milk. Lactose intolerance originates from a deficiency in the lactase enzyme. During his time at OSU, Dan has been working to find the enzyme or enzymes turning doxorubicin into doxorubicinol and to understand this chemical reaction more clearly. Past research has identified several potential enzymes, one of which being Carbonyl reductase 1 (CBR1).

Doxorubicin is converted to doxorubicinol with the addition of a single hydrogen atom.

While at OSU, Dan has ruled out other potential enzymes but has shown that when CBR1 is removed, generation of doxorubicinol is decreased but not completely eliminated, suggesting that it is one of several enzymes involved. In the lab, Dan extracts CBR1 from mouse livers, and measures its ability to produce doxorubicinol by measuring the amount of energy source consumed to carry out the process. To extract and study CBR1, Dan uses a process called “immunoclearing,” which takes advantage of the mammal’s natural immune system. Rabbits are essentially vaccinated with the enzyme of interest, in this case, with CBR1. The rabbit’s immune system recognizes that something foreign has been injected and the system creates CBR1-specific antibodies which can recognize and bind to CBR1. These antibodies are collected from the rabbits and are then used by Dan and other researchers to bind to and purify CBR1 from several fragments of mouse livers.

Prior to his time at OSU, Dan obtained a B.S. in Physics with a concentration in Biophysics from James Madison University where he also played the French horn. Realizing he loved to learn about the biological sector of science but not wanting to completely abandon physics, Dan applied to master’s programs specific to biophysics. Ultimately, Dan hopes to go to medical school. During his time at OSU, he has balanced studying for the MCAT, teaching responsibilities, course loads, research, applying to medical schools, and still finds time to play music and occasionally sing a karaoke song or two.

To hear more about Dan’s research, tune in Sunday, December 16th at 7 PM on KBVR 88.7 FM, live stream the show at http://www.orangemedianetwork.com/kbvr_fm/, or download our podcast on iTunes!

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