The Food and Drug Administration approved imatinib mesylate (Gleevec), a new oral chemotherapeutic agent, in May 2001 to treat chronic myelogenous leukemia patients (CML) who no longer respond to interferon. In February, the agency approved the drug to treat rare gastrointestinal stromal tumors. The drug has been hailed as remarkably effective in the treatment of both types of cancers.
But many questions exist about the drugs use in both diseases and in other cancers. In a review article in the Feb. 28 issue of the New England Journal of Medicine, Dr. David G. Savage, associate professor of medicine, and Dr. Karen Antman, Wu Professor of Medicine, both in the Irving Comprehensive Cancer Center, provide a comprehensive overview of the current knowledge about Gleevec. They assess when it is best to start treatment with the drug, mechanisms of drug resistance, and the probable need for combination therapy, among many other issues.
In the article, Dr. Savage observes that allogeneic stem cell transplants from a suitable donor can cure CML patients. But patients over age 40 have a greater risk from the toxic effects of chemotherapy and radiation given to ablate the patients bone marrow, from infectious complications, and from graft vs. host disease. For such older patients, Dr. Savage suggests they take interferon-alpha or Gleevec rather than proceeding directly to transplantation. Interferon therapy has been shown to prolong the survival of certain patients with CML. But as an oral medication, Gleevec is easier to take than interferon, an injectable drug. Studies in adult patients have shown Gleevec works faster and is more effective than interferon at killing leukemia cells with the Philadelphia chromosome, which is responsible for CML. A randomized trial comparing interferon (plus cytarabine) with Gleevec is under way. Dr. Savage says it remains unknown whether Gleevec will improve survival and if taking it early would compromise later allogeneic transplantation, the only known curative therapy for CML.
We also dont know how soon patients with CML will develop resistance to Gleevec and if large numbers of patients wont benefit from its use in the long-term, Dr. Savage says. If resistance is common, then doctors will have to combine it with other drugs, such as interferon. Most data on the drug are less than three years old.
Regarding gastrointestinal stromal tumors, a trial comparing doses of 400 mg with 600 mg has just closed, with data being analyzed. Gleevec currently is approved only for patients with unresectable or metastatic disease. Whether the drug should be used before or after surgery for patients at high risk for recurrence is another question that needs to be answered.
The ability of nitric oxide to regulate cerebral blood flow could depend on the blood vessels location in the brain, according to new findings from Columbia Health Sciences researchers. The research may lead to a better understanding of brain blood flow and new methods that safely deliver drugs to the brain.
In most blood vessels in the body, nitric oxide (NO) increases blood flow through the vessel by relaxing the muscles that constrict the vessel. NO also relaxes the large blood vessels on the surface of the brain. But whether NO works in the blood vessels deeper in the brain has been controversial because most human data come from patients with constricted surface vessels. Adding NO when surface vessels are constricted increases flow in deeper vessels, but the increase may only be due to the NO-induced relaxation of the surface vessels, not the deeper vessels.
In two separate studies on humans and baboons, anesthesiology and interventional radiology researchers, led by Dr. Shailendra Joshi, assistant professor of anesthesiology, looked for NOs effect on deeper vessels by examining healthy subjects with no evidence of constricted surface vessels. Using six baboons and eight humans, the researchers introduced NO into the brains blood vessels by injecting sodium nitroprusside into the carotid artery that leads to the brain. NO is generated from sodium nitroprusside in the bloodstream.
The investigators measured the blood flow by injecting a radioactive marker. Intra-arterial nitroprusside failed to increase blood flow to the brain, suggesting deep blood vessels do not respond to NO. When the surface vessels are relaxed in healthy humans and animals, regulation of blood flow deep in the brain is mainly controlled by the deeper vessels, and those do not seem to be affected by NO. The human study was published in the January issue of Anesthesiology and the baboon study was published in the February issue of Anesthesia & Analgesia.
Additional unpublished data also support the theory that NO only regulates blood flow at the surface of the brain. Large blood vessels harvested from baboon brains relaxed in response to NO addition, but deeper blood vessels did not.
Dr. Joshi says the results question the role of NO in controlling deep cerebral blood flow in both human and baboons. We are proposing that blood flow to the brain may be regulated by several mechanisms, he says. NO works very well on large arteries on the surface of the brain but does not work so well in deeper regions. Understanding the mechanisms that regulate blood flow in the brain may help identify new treatments for stroke, when blood flow to the brain is critically reduced.