Physicians and researchers know that treating tumor cells with an anticancer drug often makes cells become drug resistant — and not just to the drug being used, but to a wide range of chemotherapies. What they are unsure of is exactly how this multidrug resistance arises.
In a study appearing March 12 in the online early edition of Proceedings of the National Academy of Sciences, Susan Kane, Ph.D., professor in the Division of Tumor Cell Biology, and a team of City of Hope scientists describe a tool that may make one cause of multidrug resistance easier to see.
Researchers have previously shown that a gene called mdr1 often is to blame for multidrug resistance. The mdr1 gene produces a type of chemical called a protein pump; in normal cells, that protein pumps out toxins. Unfortunately for cancer patients, the mdr1 pump views chemotherapy drugs as toxins and pumps them out of tumor cells.
|Susan Kane, right, and Long Gu are studying one of the main causes of drug resistance in tumors. (Courtesy of Darrin S. Joy)|
And, because the mdr1 gene is sometimes turned on at very high levels in tumor cells, these cells produce much more of the mdr1 pump than other cells and move the anticancer drugs out of cancer cells quickly — long before the drugs have a chance to do any damage.
Scientists need to learn more about mdr1 to try to combat it in cancer cells. Part of their quest depends on finding a way to visualize the gene in action.
To cast some light on that, the City of Hope team enlisted help from the gene that causes fireflies to shine.
Through a feat of genetic engineering, they placed that firefly gene into the mdr1 gene in cells’ DNA. They could see when mdr1 was active in tissues by looking for glowing areas produced by the firefly gene on scans.
“The amount of glow we see in this model matches the level of mdr1 activity,” said Kane. “It gives us a new, noninvasive way to measure the activity of a gene in living systems and in real time.”
The researchers want to use the mdr1-firefly gene combination to gain a deeper understanding of how chemotherapy, toxins and even cancer development itself activate mdr1. More specifically, they want to determine which drugs activate mdr1 in particular tissues — not just in tumors but in normal organs as well, where mdr1 is important for protecting the body from foreign chemicals.
This eventually could help physicians better match their choice of treatment to specific tumor types, improving the odds for successful therapy.
“If we can determine which drugs or conditions induce mdr1-related multidrug resistance in, for instance, the breast,” said Kane, “we could potentially avoid using those drugs for a patient with breast cancer and instead use a drug that doesn’t activate mdr1.”
Kane pointed out that the firefly gene could be used to study the activity of other genes, too.
“This system is very versatile,” said Long Gu, Ph.D. “There’s no reason we can’t use a similar approach to study any number of genes involved in cancer or other diseases.” Gu is an assistant research scientist in the Division of Tumor Cell Biology and lead author on the study.
Other City of Hope researchers on the project included Walter M. Tsark, Ph.D., codirector of the Transgenic/Knockout Mouse Facility, Suzette Blanchard, Ph.D., assistant professor of biostatistics, Timothy W. Synold, Pharm.D., associate professor of clinical and molecular pharmacology, and Donna A. Brown, Ph.D., formerly in the Division of Tumor Cell Biology and now at Queen Mary’s School of Medicine and Dentistry in London.