On day 38 I wrote about side effects and how they tell you things are working. Well, there are some that overshoot that mark a little, and can cause real harm. While no side effects are great, many are temporary and can be managed, such as hair loss or a drop in white count. Others are potentially serious and long-term, such as heart damage from doxorubicin (aka adriamycin; http://en.wikipedia.org/wiki/Doxorubicin). It has been on my mind because adriamycin is the ‘A’ in ‘FAC’, the chemo cocktail I will be switching to after the holidays.
It has been known for a long time that doxorubicin (‘dox’) causes heart damage in some people, and that monitoring heart function is critical when using the drug. It was also understood that the generation of reactive oxygen species (ROS) was involved. ROS are generated in cells that are stressed or damaged, and are like little bombs that go offend cause damage to the cell’s structures. What wasn’t clear was how dox caused the damage, and why only in some people. Now comes a study from the laboratory of Dr. Yeh, chair of our Department of Cardiology, which reveals much about the mechanism of how this works.
The press release goes into excellent detail on the biology and I recommend you take a look (http://www.mdanderson.org/newsroom/news-releases/2012/key-discovered-to-how-chemotherapy-drug-causes-heart-failure.html). Here is a brief summary: doxorubicin works by inactivating toposiomerase 2, which is a cool enzyme that is involved in dealing with the challenges of keeping DNA working. If you connected all the pieces of DNA in a typical human cell it would be about 6 ft in length! Imagine that being compressed into a spot smaller than the eye can see, and you can appreciate that the DNA is very tightly packed. In fact it is compressed in an elegant hierarchy of structures, that involve lots of winding and wrapping. This is great for storage, but if you actually want to use the DNA, say to express a gene or to replicate it when a cell divides, then you have to unwrap it and later wrap it back up. Every time I get the extension cord out of my garage to put air in the tires, and it gets into the most amazing tangles and twists just by me looking at it, I think about DNA and topoisomerases and marvel at what they do. In any case, you can see that toposiomerase are needed by cancer cells as they divide and divide and divide. Inhibiting the toposiomerase forces cells to stop dividing, which normal cells can do, but which cancer cells often can’t because they lack the brakes to do so, and so crash into a form of cell death called apoptosis.
So how does inhibiting the unwrapping of DNA cause the formation of ROS? That was never clear. Now Dr. Yeh and colleagues show that in heart cells there is a form of topoisomerase 2 (called 2b) which is not found in cancer cells, and which can also be inhibited by dox. This is a classic case of a side effect being caused by a very similar mechanism as the therapeutic effect. Interestingly the generation of ROS was shown by Dr. Yeh’s group to be as a result of changes in gene expression, including ones involved in generating ROS a relatively indirect effect. This is a significant step forward that will also make it more likely that we can prevent the heart damage.
The scientists also shows that mice with high levels of the topoisomerase 2b in their cardiac cells are particularly vulnerable to heart damage, which may allow you to screen for possibly vulnerable patients. Furthermore, mice seemed to do fine without the topisomerase 2b (heart cells rarely divide) and so that suggests that you could protect patients’ hearts by lowering topo 2b levels while they are receiving dox. Clinical research based on these lab findings are already underway.
By the way, the researchers used a standard trick from the mouse genetic engineering toolbox that relies on tamoxifen triggering a reaction (here the deletion of the topo 2b gene in the mouse), but this has nothing to do with the use of tamoxifen as a drug for breast cancer. The scientists used a brief tamoxifen exposure to trigger the removal of the gene by recombination – the mice were not being treated long term with the drug to inactivate hormones.
So why does a cancer center have cardiologists? Well, in the case of MD Anderson, because we are a stand-alone cancer center, and so not integrated into a general hospital, we need those specialists in order to properly care for our patients. And because the impact of cancer on the heart is complex and specific, we see real value in having specialists that focus deeply on these questions, and are recognized world experts. And of course because they do amazing research that leads to new understanding and in the future better approaches, not only to make therapy more effective but also to reduce the side effects. So I congratulate our doctors with heart!