We propose to continue integrated studies that will correlate the pharmacokinetics, metabolism, and growth response of cerebral gliomas in humans and rats. Double-tracer autoradiographic techniques have been developed to examine tumor metabolism and brain toxicity in response to nitrosoureas in rats with experimental gliomas (C6) and AA ascites tumor. These methods allow quantitation in the brain of glucose utilization, regional cerebral blood flow, protein synthesis, and blood-brain barrier transport. Part of our research has been directed to defining tissue reactions that identify the earliest possible signs of drug toxicity. Preliminary data in 50 rats on dose-related toxicity changes in the normal brain indicate that these studies should throw light on the metabolic pattern of drug toxicity in the brain, now a limiting factor in the chemotherapy of gliomas. A study of benzodiazepine receptor binding sites in implanted rat brain tumors has been extended to evaluate differential concentration of such sites in gliomas compared to brain. Their specificity to gliomas will be studied over the short-term, and their possible role in controlling tumor tissue proliferation will be examined over the long term. The enhancing value of calcium channel antagonists in combination with nitrosoureas will be examined. The immediate aim of our proposed research is to find a reliable and non-invasive method to diagnose brain tumors, especially recurring ones, and to increase the therapeutic effectiveness of antitumor nitrosoureas. The higher tumor brain differential for SarCNU is of great interest in relation to our findings of the promising cytotoxicity of this drug. Our long-term objective is to provide a base of scientific information needed to work out more specific antitumor substances for treating malignant gliomas. Preliminary results showing higher tumor/brain uptake ratios for benzodiazepine ligand, in rat tumors and human gliomas as well as recent reports in the literature, offer the promise of developing a cytotoxic drug to target benzodiazepine receptors, thereby interfering with tumor growth.
