CELLULAR PHARMACOLOGY AND BIOLOGICAL-ACTIVITY OF 5-CARBORANYL-2'-DEOXYURIDINE

Purpose: The intracellular uptake and metabolism of 5-carboranyl-2'-de oxyuridine was investigated in primary human lymphocytes and in a T ly mphoblastoid cell line using unlabeled and tritium labeled compound. T he cytotoxicity and antiviral activity of the compound and stability t o enzyme degradation was determined. Methods and Materials: A novel me thod for radiolabeling the 5-carboranyl moiety of pyrimidine nucleosid es was developed. Cells were exposed to unlabeled and tritium labeled 5-carboranyl-2'-deoxyuridine and the intracellular uptake and egress o f the compound determined by high pressure liquid chromatography. The viability and growth of normal and malignant cells, including human an d rat gliomas, in the presence of the compound was determined. Results : Substantial levels of 5-carboranyl-2'-deoxyuridine-5'-monophosphate are formed intracellularly and this major metabolite can be detected i n cells 48 h after removal of the parent compound from the medium. No significant phosphorylation to the 5'-diphosphate or triphosphate of 5 -carboranyl-2'-deoxyuridine was detected. Furthermore, radiolabeled 5- carboranyl-2'-deoxyuridine was not incorporated into deoxyribonucleic acid. 5-carboranyl-2'-deoxyuridine was essentially nontoxic to human l ymphocytes as well as human or rat glioma cells, and had no marked eff ect in human lymphocytes acutely infected with human immunodeficiency virus type 1. Conclusion: The results demonstrate for the first time t hat 5-carboranyl-2'-deoxyuridine is phosphorylated intracellularly and suggest that it should be considered for further studies as a potenti al sensitizer for boron neutron capture therapy.