Drug Prevents Chemotherapy-Induced Hearing Loss, Study Finds
07/19/04 Portland, Ore.
A drug used to treat people with Tylenol poisoning prevents hearing loss caused by a common chemotherapy drug, an Oregon Health & Science University study reports.
The study published in the journal Hearing Research found that rats treated with N-acetylcysteine, or NAC, did not suffer from platinum-induced ototoxicity, or hearing loss, caused by a widely used chemotherapeutic agent known as cisplatin.
Cisplatin, or CDDP, is a platinum-based compound used in chemotherapy for head and neck cancer. But it causes progressive, irreversible hearing loss, reducing patients' quality of life and forcing doctors to use lower, less-effective doses of the drug.
"It affects about a third of all children with cancer in the United States, not just those with brain tumors," said study co-author Edward Neuwelt, M.D., professor of neurology and neurological surgery, OHSU School of Medicine, and the Portland Veterans Affairs Medical Center. He also directs OHSU's Blood-Brain Barrier Program. "It's a big problem."
The study's lead author, D. Thomas Dickey, D.V.M., research instructor in neurology, OHSU School of Medicine, called ototoxicity "one of the main dose-limiting factors in giving cisplatin."
"Cisplatin is given a lot. It's been around a long time, and it's very effective. But it's very toxic," Dickey said.
Cisplatin is administered intravenously to slow or stop the growth of cancer cells. In addition to head and neck cancers, the drug is used to treat cervical carcinoma, lung cancer, neurologic cancers and a wide variety of other malignancies. But it injures hair cells of the cochlea, the spiral, inner-ear structure containing thousands of tiny hair cells that vibrate in response to sound waves.
"These hair cells are often destroyed," Dickey said. "It starts at the outer edge and moves in. Once it happens, it's progressive -- it gets worse and worse -- and it's permanent."
Hearing aids aren't as effective in young children with ototoxicity because they haven't developed language skills before they lose hearing and, as a result, don't know what to listen for. As a result, many children become depressed and socially isolated, and they fall behind in school.
"Their whole development suffers because of it," Dickey said. "The higher frequencies are affected first, and often it's right in the frequency of human speech."
Scientists believe NAC, occasionally sold as an amino acid supplement to treat bronchitis, cystic fibrosis and other respiratory illnesses, prevents ototoxicity by binding to the cisplatin platinum molecules, rendering them inactive. It also is a known free radical scavenger, hunting down these highly reactive atom clusters believed to cause similar hearing loss caused by noise trauma, and it boosts levels of an intracellular antioxidant called glutathione.
"We know that NAC can get into the cells by entering some metabolic pathways, and it may actually increase the way a cell protects itself," said Leslie Muldoon, Ph.D., assistant professor of neurology, and cell and developmental biology, OHSU School of Medicine.
But because NAC can turn off cisplatin's active element, platinum, the timing of its use is everything. The study found that NAC was most effective against cisplatin when given 15 minutes before chemotherapy, but it was less likely to diminish cisplatin's cancer-fighting effects when given 30 minutes before or four hours after chemotherapy.
"The reason we don't want to give (NAC) right before the chemotherapy is it's going to take the chemotherapeutic effect away from the tumor," Muldoon said. "We'd really like to protect hearing without protecting the tumor."
NAC also appears to protect against other side effects of cisplatin use, such as gastrointestinal and renal toxicity. In fact, rats given NAC 15 minutes before chemotherapy exhibited less overall toxicity, shown as weight loss, seven days after treatment.
"They all lose weight, but it's significantly less" following NAC treatment, Dickey said.
Researchers will continue to study different timings, doses and methods of delivering NAC to improve its chemoprotective effects while assuring enough active cisplatin reaches tumors.
Meanwhile, clinical trials are ongoing and new ones are being developed using both NAC and another sulfur-containing drug called sodium thiosulfate (STS), both at OHSU and in collaboration with national organizations such as the Children's Oncology Group.
Dale Kraemer, Ph.D., assistant professor of medical informatics and clinical epidemiology, OHSU School of Medicine, provided statistical analysis for the study. The study was funded by the National Institutes of Health and the Veterans Administration.
OHSU and Drs. Neuwelt and Muldoon have a significant financial interest in Adherex, a company that may have a commercial interest in the results of this research. This potential conflict of interest has been reviewed and managed by the OHSU Conflict of Interest in Research Committee.