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Cellular Influx, Efflux, and Anabolism of 3-Carboranyl Thymidine Analogs: Potential Boron Delivery Agents for Neutron Capture Therapy
Faculty
Science
Year:
2013
Type of Publication:
Article
Pages:
388-397
Authors:
Sjuvarsson, Elena, Damaraju, Vijaya L, Mowles, Delores, Sawyer, Michael B, Tiwari, Rohit, Agarwal, Hitesh K, Khalil, Ahmed, Hasabelnaby, Sherifa, Goudah, Ayman, Nakkula, Robin J, Barth, Rolf F, Cass, Carol E, Eriksson, Staffan, Tjarks, Werner
DOI:
10.1124/jpet.113.207464
Journal:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
Volume:
347
Research Area:
Pharmacology \& Pharmacy
ISSN
ISI:000325934400015
Keywords :
Cellular Influx, Efflux, , Anabolism , 3-Carboranyl Thymidine
Abstract:
3-{[}5-\{2-(2,3-Dihydroxyprop-1-yl)-o-carboran-1-yl\}pentan-1-yl]thymidi ne (N5-2OH) is a first generation 3-carboranyl thymidine analog (3CTA) that has been intensively studied as a boron-10 (B-10) 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.
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