Sean Henahan

WASHINGTON, DC- A landmark clinical study of sickle cell anemia has been halted prematurely following unexpected success with an "off the shelf" anti-cancer agent.

Three hundred patients with severe sickle cell anemia participated in the "Multicenter Study of Hydroxyurea in Sickle Cell Anemia ". The patients received daily doses of either an anti-cancer drug called hydroxyurea or a placebo for up to 18 months. The study was halted early so that placebo recipients could also receive the benefits observed in the other patients.

The group of patients receiving hydroxyurea showed a 50% reduction in the frequency of painful episodes and hospital admissions compared with patients receiving the placebo. The patients receiving hydroxyurea therapy also showed significant reductions in the frequency of chest pain, fever, and abnormal chest X-rays. Patients taking hydroxyurea also had approximately 50 percent fewer cases of acute chest syndrome and required about 50 percent fewer units of blood transfused than patients on the placebo.

"This is a significant advance in the treatment of adults with sickle cell anemia. Although it is not a cure, hydroxyurea therapy is the first effective treatment for this serious illness and may greatly improve the quality of life of sickle cell anemia patients." said Dr. Claude Lenfant, Director, National heart Lung and Blood Institute.

Scientists are not sure why the drug works. The leading hypothesis is that hydroxyurea may work by stimulating the production of fetal hemoglobin (the type of hemoglobin people are born with, some of which remains in adult blood). The researchers believe that fetal hemoglobin inside sickled red blood cells may prevent those cells from becoming rigid, thereby preventing blood vessel obstruction and the resulting pain and side effects.

Sickle cell anemia is an inherited disease that is most common among people whose ancestors come from Africa, the Middle East, the Mediterranean basin, and India. In the U.S., it affects primarily African Americans, about 72,000 of whom have the disease. One in 12 African Americans carries the sickle cell trait. Homozygotes, about 0.3% of African Americans, have the disease. In addition, approximately 10% of African Americans are heterozygotes in whom the sickling trait can be demonstrated, although no symptoms are present.

The red blood cells of people with sickle cell disease contain an abnormal type of hemoglobin, the oxygen-carrying pigment, called hemoglobin S. The deficiency of oxygen in the blood causes hemoglobin S to crystallize, distorting the red blood cells into a sickle shape, making them fragile and easily destroyed, leading to anemia.

The "sickled" blood cells then are unable to squeeze through the smaller blood vessels (arterioles and capillaries). When the tissues are deprived of an adequate blood supply, painful symptoms occur. Complications can include stroke, bone pain, kidney damage and breathing problems. The recurrent pain caused by the disease interferes with many aspects of the patients' lives including education, employment, and psychosocial development.

Hydroxyurea is currently used to create certain types of cancers and a blood disorder known as polycythemia vera, a disease in which too many red blood cells are produced. Because the drug has been used clinically for 30 years, its safety profile is well understood. Hydroxyurea is believed to inhibit DNA synthesis by inhibiting synthesis of oxynucleotides, all without inhibiting synthesis of RNA. The drug is often given concomitantly with radiation therapy for cancers of the head and neck. It is also used to treat certain leukemias and ovarian carcinoma. In vitro studies suggest hydroxyurea kills S-stage cells and keeps other cells locked in the G1, pre-DNA synthesis stage. It is also hypothesized that hydroxyurea hinders the replication of cells already damaged by radiation therapy.

In another study reported in Science Update earlier this year, scientists reported promising in vitro data suggesting an anti-HIV effect for hydroxyurea. That study appeared in Science- Nov.4, '94, Lori et al, p. 801.

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