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M9460297.TXT
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1994-06-12
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Document 0297
DOCN M9460297
TI Cellular pharmacology and biological activity of
5-carboranyl-2'-deoxyuridine.
DT 9408
AU Schinazi RF; Goudgaon NM; Fulcrand G; el Kattan Y; Lesnikowski Z; Ullas
G; Moravek J; Liotta DC; Veterans Affairs Medical Center (Atlanta),
Decatur, GA 30033.
SO Int J Radiat Oncol Biol Phys. 1994 Mar 30;28(5):1113-20. Unique
Identifier : AIDSLINE MED/94230028
AB PURPOSE: The intracellular uptake and metabolism of
5-carboranyl-2'-deoxyuridine was investigated in primary human
lymphocytes and in a T lymphoblastoid cell line using unlabeled and
tritium labeled compound. The cytotoxicity and antiviral activity of the
compound and stability to enzyme degradation was determined. METHODS AND
MATERIALS: A novel method for radiolabeling the 5-carboranyl moiety of
pyrimidine nucleosides was developed. Cells were exposed to unlabeled
and tritium labeled 5-carboranyl-2'-deoxyuridine and the intracellular
uptake and egress of the compound determined by high pressure liquid
chromatography. The viability and growth of normal and malignant cells,
including human and 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 in 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 lymphocytes as well as human or rat
glioma cells, and had no marked effect in human lymphocytes acutely
infected with human immunodeficiency virus type 1. CONCLUSION: The
results demonstrate for the first time that 5-carboranyl-2'-deoxyuridine
is phosphorylated intracellularly and suggest that it should be
considered for further studies as a potential sensitizer for boron
neutron capture therapy.
DE Boron Compounds/CHEMICAL SYNTHESIS/*METABOLISM/PHARMACOLOGY *Boron
Neutron Capture Therapy Cell Survival/DRUG EFFECTS Cells, Cultured
Deoxyuridine/*ANALOGS & DERIVATIVES/CHEMICAL SYNTHESIS/METABOLISM/
PHARMACOLOGY Human Phosphorylation Radiation-Sensitizing
Agents/*METABOLISM Support, U.S. Gov't, Non-P.H.S. Support, U.S.
Gov't, P.H.S. JOURNAL ARTICLE
SOURCE: National Library of Medicine. NOTICE: This material may be
protected by Copyright Law (Title 17, U.S.Code).