Biomedical Frontiers: SPRING/SUMMER 1997, Vol.4, No.3
Better Drug Delivery

researchers at CPMC are par-ticipating in a multi-center NIH clinical trial of a new system that delivers drugs directly to the site of a brain tumor. The system, called intracerebral clysis, also holds promise as a gene delivery method for genetic therapy.

Most of the 15,000 people diagnosed with brain tumors each year have malignant gliomas, says Dr. Jeffrey Bruce, associate professor of neurosurgery and director of the Brain Tumor Research Laboratory. The outlook for these individuals is bleak: Most are young and otherwise healthy, and tumors cause severe neurologic disabilities. Even with intensive treatment, the median survival time for brain cancer is one year.

In intracerebral clysis, scientists use a CT scan and a computer program to place a catheter directly into the brain tumor. They can then deliver chemotherapeutic agents directly to the tumor at a low but constant flow rate of several drops per hour. This allows researchers to deliver a high concentration of drugs to the brain, an area that chemotherapy might not otherwise reach because of the blood-brain barrier.

Researchers at NIH and Nycomed Pharmaceuticals have developed a targeted protein toxin known as HN-66000 to treat brain tumors. The toxin consists of a conjugate of a modified diphtheria toxin joined to human transferrin. Glioblastoma cells express high concentrations of transferrin receptors on their surface. When the transferrin binds to its receptor, the toxin catalyzes the inactivation of protein synthesis, resulting in cell death. HN-66000 has been tested in in vitro studies, animal models, and phase I clinical trials and will now be tested in phase II clinical trials, in which CPMC researchers Drs. Bruce, Michael Fetell, Casi Balmaceda, and Michael Sisti will participate.

In addition, Dr. Bruce and colleagues at the Brain Tumor Research Laboratory are investigating the delivery of other drugs via intracerebral clysis using a model system in a rat. "This method opens up the use of drugs and compounds that would not reach the brain because they would break down in the liver or the blood," says Dr. Bruce. Proteins, enzymes, and other molecular biologic compounds are a few such possibilities.