BORON-CONTAINING ISOQUINOLINES AND BENZOIDIAZEPINES FOR TARGETING GLIOMA CELLS

BORON NEUTRON-CAPTURE THERAPY (BNCT) IS A BINARY SYSTEM FOR DELIVERING INTENSELY IONIZING RADIATION TO TUMORS USING A COMBINATION OF BORON-10 LABELED MOLECULES AND THERMAL NEUTRONS TO ACHIEVE A TUMORCIDAL EFFECT. RECENT EVIDENCE HAS INDICATED THAT THERE ARE PERIPHERAL BENZODIAZEPINE- BINDING SITES (PBS) ON VIABLE TUMOR CELLS TO WHICH COMPOUNDS CAN BE SPECIFICALLY BOUND AND THAT THESE STRUCTURES DO NOT BECOME ATTACHED TO THE NECROTIC TUMOR OR THE NORMAL CEREBRAL CORTEX. LIGANDS THAT ARE CAPABLE OF BINDING SELECTIVELY TO PBS ACHIEVE HIGH CONCENTRATION LEVELSON MALIGNANT CELLS. SUCH A LIGAND IS THE BENZODIAZEPINE ANTAGONIST PK 11195, A SUBSTITUTED ISOQUINOLINE. THE INITIAL OBJECTIVE OF PHASE I WILL BE TO SYNTHESIZE A BORON-CONTAINING ISOQUINOLINE THAT IS STRUCTURALLY RELATED TO PK 11195 AND EVALUATE IT AGAINST MALIGNANT GLIOMA CELLS, F98 ANAPLASTIC RAT TUMOR. IF THESE STUDIES ARE SUCCESSFUL AND SUCH COMPOUNDS ARE USEFUL IN TARGETING GLIOMA CELLS UNDER IN-VITRO CONDITIONS, THEN THEIR EVALUATION UNDER IN-VIVO CONDITIONS IN TUMOR-BEARING ANIMALS WOULD BE UNDERTAKEN. THE SELECTIVE DESTRUCTION OF TUMOR AND TUMOR FOCI USING SUCH TECHNIQUES WOULD HAVE A SIGNIFICANT IMPACT ON THE COURSE OF TREATMENT OF PATIENTS WITH DIAGNOSED MALIGNANT GLIOMAS.