Longitudinal analysis of the most recently available data from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program demonstrated a dramatic rise in the age-specific incidence of primary malignant brain tumors in the elderly between 1973 and 1985,. in the United States. Primary malignant brain tumors have perhaps the worst prognosis of all cancers. They are invariably-fatal, with a median survival time of approximately 10 months. .Rational strategies were developed to improve the treatment of malignant brain tumors. A novel lipophilic anticancer alkylating agent, a tertiary butyl ester of chlorambucil, was developed for brain tumor treatment. It, has a high delivery to brain and efficacy against brain tumor cells. Further, a blood-brain barrier opening technique was developed to increase the brain delivery of water-soluble therapeutic agents. The intracarotid infusion of a hypertonic solution of either mannitol or L-arabinose causes transient and innocuous barrier opening allowing increased uptake of therapeutics and intravascular markers into brain. A mathematical model describing drug uptake into brain tumors, directly from blood and indirectly from neighboring tissue, was developed and used to quantitate the effectiveness of the osmotic method. The factors that codetermine the amount of drug that enters and is maintained in brain following its systemic administration were analyzed to aide in the development of central nervous system therapeutics.
