The drug, called decitabine, works even in patients who don't respond to hydroxyurea, the standard treatment, and appears to produce fewer side effects.
"The results of our study are compelling," said Joseph DeSimone, professor of hematology and oncology and a member of the UIC Cancer Center. "Clearly, decitabine is an effective therapy for patients who do not benefit from the traditional treatment. It is possibly even an improvement, although more studies will have to be done."
The clinical trial was conducted at the University of Illinois Medical Center at Chicago, which houses the area's only clinic specializing in sickle cell disease. Results of the study will appear in the June 1 issue of the scientific journal Blood.
Sickle cell disease is caused by a single mutation in a gene that manufactures hemoglobin, the molecule in red blood cells that delivers oxygen to tissues throughout the body.
The defective form of hemoglobin, called hemoglobin S (for sickle), causes serious health problems. Red blood cells take on a characteristic crescent, or sickle, shape and stick to blood vessel walls.
As a result, the cells cannot squeeze through capillaries. Blood supply is blocked, depriving tissues and organs of oxygen and causing short- and long-term damage. Patients suffer episodes of intense pain, typically in the arms, legs and back, but also in the liver, kidney and abdomen.
In some severe cases, transfusions may be required because the aberrant red blood cells have a much shorter life span than normal red blood cells (10 days vs. 100) and the body can't manufacture enough new red blood cells to keep up, leading to anemia.
Patients may also suffer what is called acute chest syndrome, a particularly serious complication and the leading cause of death in sickle cell disease. Symptoms include rapid or labored breathing, accompanied by lung infection.
"Like hydroxyurea, decitabine works by turning the production of fetal hemoglobin back on," DeSimone explained.
A type of hemoglobin found in the fetus but almost absent in a person's blood stream by the age of one year, fetal hemoglobin inhibits certain changes in the hemoglobin S molecule that cause the sickling of the cell. Increasing the patient's production of fetal hemoglobin results in a decrease in the severity of sickle cell symptoms. Patients have fewer episodes of pain and acute chest syndrome, require hospitalization less frequently and need blood transfusions less often.
Building on earlier clinical trials of the drug at UIC, DeSimone and his colleagues treated eight patients who did not respond to hydroxyurea with low doses of decitabine (0.15 to 0.30 mg/kg/day). After nine months of treatment, the therapy succeeded in maintaining fetal hemoglobin levels at close to 20 percent of all hemoglobin circulating in the patients' blood -- levels considered sufficient for optimal therapeutic effects.
While hydroxyurea causes a decline in the production of all types of blood cells -- a major side effect of the drug -- blood samples taken after decitabine treatment showed only a small decline in infection-fighting cells, with levels still in the normal range. No decreases were seen in the levels of any other blood cells.
According to DeSimone, future studies will concentrate on reducing the interval between doses to increase the levels of fetal hemoglobin and increasing the length of time patients are on the drug to ensure that harmful side effects do not emerge with time. An oral form of decitabine is in development.
Sickle cell disease is found primarily in populations originating in the world's malarial belt. About one in 500 African-Americans suffers from the disease. Illinois has approximately 5,000 sickle cell patients, 85 percent of whom reside in Cook County -- one of the country's highest concentrations of sickle cell patients.
Decitabine was supplied by SuperGen Inc., which supported this study.
Other authors of the study were UIC researchers Louise Dorn, Donald Lavelle, Linda Bressler, Robert Molokie, as well as Mabel Koshy and Nasrin Talischy, formerly of UIC.
For more information about UIC, visit www.uic.edu.
Journal
Blood