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Crossing Over

Hippocrates, the father of modern medicine who lived between 460 and 377 B.C., had records of a powder made from the bark and leaves of the willow tree that would relieve headache pain and fever.

Over the centuries, this natural remedy evolved into the wonder drug commonly known as aspirin.

Nearly 2,000 years later, a physician named Lawrence Craven determined that none of his 8,000 male patients who took a daily aspirin for six years had suffered a heart attack.

Although Craven’s study took place in the early 1950s, the Food and Drug Administration did not approve the use of aspirin to prevent recurrent heart attack and stroke until 1985.

Today, new data show that aspirin is an effective treatment for strokes, certain vascular conditions and rheumatologic diseases. It also has been linked to the prevention of pre-cancerous growths in the colon and common complications of diabetes resulting from impaired blood circulation.

Aspirin is just one of the countless crossover drugs now used to treat diseases or symptoms far beyond their original intent. Many have been proven effective for seemingly disparate – but often related – biological systems or disease states.

Several chemotherapy drugs that have been successfully used to treat cancer have become crossover drugs now used in the treatment of specific autoimmune disorders and viruses, said Stan Louie, associate professor of clinical pharmacy in the USC School of Pharmacy.

One cancer drug is methotrexate, now commonly used to treat such autoimmune disorders as rheumatoid arthritis (RA), psoriatic arthritis and lupus.

Autoimmune disorders cause a person’s immune system to attack itself, causing pain or inflammation in or around the tissues, bones and muscles surrounding the joints.

In these diseases, immune cells are replicating quickly, which causes overly reactive white blood cells to attack connective tissue, Louie said.

“Low doses of methotrexate affect specific types of white blood cells, called macrophages, which engulf foreign material in the body and initiate the autoimmune response,” he said. “Methotrexate suppresses these macrophages, making it possible to lessen or prevent an autoimmune reaction, thus reducing inflammation and pain.”

Methotrexate’s secondary benefits were discovered when cancer patients with RA began to see a remarkable reduction in joint pain and inflammation, said Nouri Neamati, assistant professor of pharmaceutical sciences in the USC School of Pharmacy.

“Researchers generally do not know about secondary therapeutic uses for a drug until it gets to patients in the clinic,” Neamati said.

The advent of the selective estrogen receptor modulators (SERMs) – such as tamoxifen and raloxifene – has strengthened medical practitioners’ arsenal against both breast cancer and osteoporosis.

SERMs work by binding to selective estrogen receptors in the bones, just like estrogen does. At the same time, they block the effects of estrogen on breast tissue.

“Estrogen is a stimulating growth factor for certain kinds of breast cancers, and long-term use has been correlated with an increased risk of uterine cancer,” Louie said.

“An ideal SERM would block the negative effects of estrogen on breast and uterine tissue, while enhancing its effect on a patient’s skeletal and cardiovascular system.”

The FDA has approved tamoxifen for the prevention and treatment of breast cancer in women who are at high risk for the disease.

An unfortunate drawback to tamoxifen is an increased risk of uterine cancer and blood clots for women. Although it is thought to help protect bone density, tamoxifen has not been approved to prevent osteoporosis, he said.

On the other hand, the FDA has approved raloxifene for the prevention of osteoporosis. Its crossover application – deterring cancer – became apparent during testing for its activity against osteoporosis, Louie said.

“It was determined that women in the anti-osteoporotic study of raloxifene developed fewer breast cancer tumors without an increased risk of uterine cancer,” he said. “This sparked the idea for a clinical trial to quantify raloxifene’s effect on cancer prevention.”

The Study of Tamoxifen and Raloxifene (STAR) clinical trials are currently underway at cancer centers across the country, including the USC/Norris Comprehensive Cancer Center. Principal investigator Darcy Spicer, associate professor of clinical medicine the Keck School, is following postmenopausal women who are at high risk for breast cancer to determine if raloxifene is as effective in preventing breast cancer as tamoxifen has proven to be.

If raloxifene is found to protect against both breast cancer and osteoporosis, it may replace tamoxifen as a therapeutic option for the prevention of these diseases, Louie said.

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