The ideal substance to prevent cancer would block tumor growth without causing unpleasant or dangerous side effects. Researchers at Washington University School of Medicine in St. Louis now report that a compound related to vitamin A shows promise in preventing or slowing tumor growth in mice prone to lung cancer. The compound, called bexarotene, doesn't cause the severe skin irritations that have limited the use of other vitamin A derivatives in cancer therapies.
"In the cancer prevention field, you look for drugs that can be given to healthy patients who have a higher risk of developing cancer," says Ming You, M.D., Ph.D., director of the Chemoprevention Program at the Siteman Cancer Center. "These patients wouldn't want to take a medication that makes them feel sick when they don't have cancer. So the drugs should be very well-tolerated and not cause harmful side effects."
In other studies, bexarotene showed some promise in cancer treatment. It extended survival in patients with non-small cell lung cancer, the most common type of lung cancer and one that has a five-year survival rate of less than 5 percent when diagnosed at the advanced stage.
In the current study, due to appear in an upcoming issue of Oncogene, Yian Wang, M.D., Ph.D., associate professor of surgery, You, professor of surgery, and colleagues demonstrate that lung-cancer-susceptible mice receiving non-toxic doses of bexarotene ended up with fewer and smaller benign and malignant tumors than mice that were not treated with bexarotene. The researchers saw a reduction of almost 50 percent in terms of total tumor burden in mice who were given bexarotene for 12 weeks after the animals had already developed benign tumors following injection of a lung carcinogen. Bexarotene also inhibited the progression of benign to malignant tumors by about 50 percent. The mice were engineered to have the genetic alterations seen in human lung cancers, so they readily develop lung cancer when given known lung carcinogens.
"Seeing this magnitude of response in such a strongly susceptible mouse suggests bexarotene is a potentially viable lung cancer prevention candidate," You says.
Vitamin A analogs called retinoids have been studied for several years as potential chemotherapeutic agents because they help regulate cell division, growth, differentiation and proliferation. A new class of these vitamin A relatives has been created that includes bexarotene. These substances are called the rexinoids, so named because they are attracted to a molecule on cell surfaces called RXR.
Rexinoids tend to be much less toxic than retinoids, and among them bexarotene has so far shown the most promise as a chemopreventive medicine. However, although it causes far fewer side effects, bexarotene does have the effect of increasing blood lipid levels in many patients. Patients taking bexarotene often need to take a drug to lower their cholesterol and triglyceride levels.
A new rexinoid called UAB30, just becoming available for laboratory studies, seems to have the potential to reduce even the high-lipid side effect.
"We will be testing this new compound, too, and if it turns out to be effective, these rexinoids will most likely become candidates for clinical trials in patients with precancerous nodules or bronchial dysplasia," You says. "If the trials show reduction of cancers, I think these drugs may well become routinely used for lung cancer prevention." Prevention is considered vital to decreasing the impact of lung cancer, which accounts for 32 percent of cancer deaths in men and 25 percent of cancer deaths in women. The majority of lung cancer patients are not diagnosed until their cancer has reached an advanced stage, and current treatment regimens do not substantially improve the outcome for most of these patients.
"Advanced or metastatic cancer is sort of a genius at adapting," You says. "By that point, the cancer cells that have survived have overcome so many obstacles and gained so many abilities that they are difficult to kill. They have a very unstable genome that can change quickly to resist the treatments we use. It's best if you attack cancer in its infancy or at the precancerous stage. The earlier the better."
Wang Y, Zhang Z, Yao R, Jia D, Wang D, Lubet RA, You M. Prevention of lung cancer progression by bexarotene in mouse models. Oncogene 2006.
Funding from the National Institutes of Health supported this research.
Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Siteman Cancer Center is the only NCI-designated Comprehensive Cancer Center within a 200-mile radius of St. Louis. Siteman Cancer Center is composed of the combined cancer research and treatment programs of Barnes-Jewish Hospital and Washington University School of Medicine.
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