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Cellular influx, efflux, and anabolism of 3-carboranyl thymidine analogs: potential boron delivery agents for neutron capture therapy.

Abstract
3-[5-{2-(2,3-Dihydroxyprop-1-yl)-o-carboran-1-yl}pentan-1-yl]thymidine (N5-2OH) is a first generation 3-carboranyl thymidine analog (3CTA) that has been intensively studied as a boron-10 ((10)B) delivery agent for neutron capture therapy (NCT). N5-2OH is an excellent substrate of thymidine kinase 1 and its favorable biodistribution profile in rodents led to successful preclinical NCT of rats bearing intracerebral RG2 glioma. The present study explored cellular influx and efflux mechanisms of N5-2OH, as well as its intracellular anabolism beyond the monophosphate level. N5-2OH entered cultured human CCRF-CEM cells via passive diffusion, whereas the multidrug resistance-associated protein 4 appeared to be a major mediator of N5-2OH monophosphate efflux. N5-2OH was effectively monophosphorylated in cultured murine L929 [thymidine kinase 1 (TK1(+))] cells whereas formation of N5-2OH monophosphate was markedly lower in L929 (TK1(-)) cell variants. Further metabolism to the di- and triphosphate forms was not observed in any of the cell lines. Regardless of monophosphorylation, parental N5-2OH was the major intracellular component in both TK1(+) and TK1(-) cells. Phosphate transfer experiments with enzyme preparations showed that N5-2OH monophosphate, as well as the monophosphate of a second 3-carboranyl thymidine analog [3-[5-(o-carboran-1-yl)pentan-1-yl]thymidine (N5)], were not substrates of thymidine monophosphate kinase. Surprisingly, N5-diphosphate was phosphorylated by nucleoside diphosphate kinase although N5-triphosphate apparently was not a substrate of DNA polymerase. Our results provide valuable information on the cellular metabolism and pharmacokinetic profile of 3-carboranyl thymidine analogs.
AuthorsElena Sjuvarsson, Vijaya L Damaraju, Delores Mowles, Michael B Sawyer, Rohit Tiwari, Hitesh K Agarwal, Ahmed Khalil, Sherifa Hasabelnaby, Ayman Goudah, Robin J Nakkula, Rolf F Barth, Carol E Cass, Staffan Eriksson, Werner Tjarks
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 347 Issue 2 Pg. 388-97 (Nov 2013) ISSN: 1521-0103 [Electronic] United States
PMID24006340 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • 3-(5-(2-(2,3-dihydroxyprop-1-yl)-o-carboran-1-yl)pentan-1-yl)thymidine
  • ABCC4 protein, human
  • Boron Compounds
  • Multidrug Resistance-Associated Proteins
  • Nucleoside Transport Proteins
  • Thymidine Kinase
  • thymidine kinase 1
  • Thymidine
Topics
  • Animals
  • Biological Transport
  • Boron Compounds (administration & dosage, chemistry, metabolism, pharmacology)
  • Boron Neutron Capture Therapy (methods)
  • Cell Line
  • Cell Survival (drug effects)
  • Humans
  • Mice
  • Molecular Structure
  • Multidrug Resistance-Associated Proteins (metabolism)
  • Nucleoside Transport Proteins (genetics, metabolism)
  • Phosphorylation
  • Saccharomyces cerevisiae (genetics)
  • Substrate Specificity
  • Thymidine (administration & dosage, analogs & derivatives, chemistry, metabolism, pharmacology)
  • Thymidine Kinase (metabolism)
  • Transfection

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