Painful bladder disorder affects about 1 million people, mostly women
In what may be a major breakthrough in understanding a chronic painful bladder disorder known as interstitial cystitis (IC), researchers at the University of Maryland School of Medicine, in collaboration with investigators at the National Cancer Institute, have completed the first total description of the structure of a toxin known as antiproliferative factor (APF).
This toxin, which is found in the urine of approximately 95 percent of IC patients, appears to be specific for this disorder. It inhibits the growth of bladder epithelial cells, which may explain why those with IC have a disorder distinguished by thinning or ulceration of the bladder’s inner lining or epithelium. The researchers say that knowing details about this toxin, which they had earlier identified, may lead to a diagnostic test for IC.
The study will be published online this week in the early edition of the Proceedings of the National Academy of Science; in August, the study will appear in print.
“We don’t know what causes interstitial cystitis, and until now we have not had a good diagnostic tool,” says Susan K. F. Keay, M.D., Ph.D., principal investigator of the study and professor of medicine and pathology at the University of Maryland School of Medicine. “Now that we know the structure of the toxin, and we’ve been able to produce it synthetically, we plan to use the synthetic toxin to develop a diagnostic test for this disorder, using urine or serum samples," adds Dr. Keay, who is also a staff physician for the VA Maryland Health Care System.
Determination of the structure of the toxin and its total chemical synthesis was carried out in collaboration with a team of scientists at the National Cancer Institute’s Center for Cancer Research, led by Christopher J. Michejda, Ph.D.
Approximately 1 million people in the United States suffer from interstitial cystitis, and 90 percent of them are women. There is no cure. Symptoms include pain in the bladder or surrounding areas of the urinary tract, as well as increased frequency and urgency of urination. People with severe symptoms may urinate as many as 60 times a day. Symptoms resemble urinary tract infections, but they generally do not go away. Symptoms may wax and wane, but only about 10 percent of patients with IC will ever have their symptoms disappear.
Diagnosis is difficult, because infection and a wide range of urinary tract disorders including bladder cancer, bacterial cystitis, sexually transmitted diseases and, in men, prostatitis, must first be ruled out. Treatment is aimed at relieving symptoms.
According to Dr. Keay, the toxin occurs in tiny quantities in urine from people with IC, but does not appear to be present in urine from people with a normal bladder. The toxin is a type of peptide or small protein that puts the epithelial cells in the inner lining of the bladder into a state of suspended animation. The cells cannot grow or proliferate by dividing to form new cells. “We know that if you put the APF toxin on normal bladder cells, it keeps them from growing,” says Dr. Keay. “But once you remove it, after a week to 10 days, the cells can resume their normal growth. So it’s truly an antiproliferative factor.”
According to Dr. Michejda, “It was important to achieve the total chemical synthesis of the APF toxin, because that firmly established the structure of the APF toxin and also provided large enough quantities of the toxin for the development of diagnostic tools.” The synthetic APF toxin acts the same as APF toxin purified from the urine of patients with IC.
Dr. Keay’s team is also working to develop an animal model based on the APF toxin, in order to test the toxin as a cause of this disorder. “An animal model will tell us if the toxin by itself can cause the changes in bladder tissue seen in IC,” says Dr. Keay.
The toxin inhibits a certain growth factor required for the development of bladder epithelial cells. Dr. Keay says knowing the effect of the toxin on that growth factor is important because one possible treatment path may involve reversing the action of the APF toxin.
Dr. Keay’s team has found that the effect of the toxin could be totally overcome by adding a genetically engineered form of the growth factor to cell cultures in concentrations that are normally found in human urine. “By adding the growth factor, we essentially overcame the toxic effect of the APF toxin,” Dr. Keay says.
But she cautions that the genetically engineered form of this growth factor can stimulate the growth of tumor cells once they have started growing on their own. “Obviously there are safety factors that have to be addressed before something like that can be used as a treatment for this disorder,” says Dr. Keay.
Working with investigators in Dr. Michejda’s laboratory at the National Cancer Institute, the University of Maryland researchers will attempt to identify other compounds that may directly inhibit the action of the toxin, without harmful side effects. Their future research will focus not only on the development of a rapid and accurate diagnosis of IC but also on possible new therapies for the disease.
Dr. Keay says one other significant finding of the current study is that the APF toxin is a tiny fragment of a protein called a “frizzled 8” protein, one of a class of proteins that has been linked to other diseases, including a form of heart failure and degenerative retinal disease. “We want to understand why these cells are making this small segment,” says Dr. Keay. “No one knows if the frizzled 8 protein plays any role in bladder epithelial cells. It’s also not known whether the whole protein or this fragment is expressed during the development of normal epithelium. We hope to determine that.”
Funding for the study was provided by the National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases, National Cancer Institute), the Department of Veterans Affairs and the Interstitial Cystitis Association/Fishbein Foundation.
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