Primary central nervous system (CNS) malignancy is second only to leukemia as the leading cause of cancer death among children younger than 15 years of age. Among men 15 to 54 years old, brain tumors are the third most frequent cause of death, and among women 15 to 34 years old, brain tumors are the fourth most frequent cause of cancer death. Although primary brain cancer is a relatively rare disease when compared to the incidence of all forms of cancer, approximately 15,000 new cases will occur in the United States in 1989. The many other forms of cancer that metastasize to the brain significantly increase the total incidence of patients with brain tumors. The University of California, San Francisco (UCSF) is a major treatment center for patients with cancer of the CNS, and the most common type of tumor diagnosed at the UCSF hospitals is a neurological malignancy. During 1988 about 400 surgical procedures for brain tumors were performed in the UCSF Department of Neurological Surgery, the Neuro-oncology Service of the Brain Tumor Research Center (BTRC) had over 2,000 patient visits, and our oncologists saw about 400 new patients for consideration of entry into clinical trials. This proposal is based on two general hypotheses: The first is that polyamine inhibitors and analogs can be used to manipulate intracellular polyamines in such a way that tumor cell growth will be inhibited, that tumors cells will be killed, and/or that the tumor cells will be more susceptible to other treatment modalities - particularly to irradiation, hyperthermia, and chemotherapy with BCNU. The second is that, by depleting the natural levels of polyamines in the area of brain affected by the tumor, polyamine inhibitors and analogs can halt the expansion of necrosis and edema that tumor irradiation causes in normal brain. We anticipate that findings from our basic research in these two areas should be directly applicable to new therapeutic approaches on our Neuro-oncology Service. Six projects and 2 cores are proposed: 1) Clinical Therapy for Malignant Brain Tumors; 2) Polyamine-DNA Interactions: An Approach to the Development of Therapeutic Agents; 3) Modification of Radiation Recovery Human Brain Tumor Cells by Polyamine Damage in Normal Brain; 6) The Importance of Vasogenic Edema in the Genesis of Late Delayed Radiation Injury of the Rat Spinal Cord; 7) Cell and Tissue Bank Core; and, 8) Administrative Core. Pursuit of the basic science projects (2-6) will provide relevant information for the planning and implementation of clinical trials conducted in Project 1, and the outcome of the clinical trials will pose additional questions to the basic scientists.
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