Thymidine kinase 1 as a molecular target for boron neutron capture therapy of brain tumors

Rolf F. Barth, Weilian Yang, Gong Wu, Michele Swindall, Youngjoo Byun, Sureshbabu Narayanasamy, Werner Tjarks, Kevin Tordoff, Melvin L. Moeschberger, Staffan Eriksson, Peter J. Binns, Kent J. Riley

Research output: Contribution to journalArticle

Abstract

The purpose of the present study was to evaluate the effectiveness of a 3-carboranyl thymidine analogue (3CTA), 3-[5-{2-(2,3-dihydroxyprop-1-yl)-o- carboran-1-yl}pentan-1-yl] thymidine, designated N5-2OH, for boron neutron capture therapy (BNCT) of brain tumors using the RG2 rat glioma model. Target validation was established using the thymidine kinase (TK) 1(+) wild-type, murine L929 cell line and its TK1(-) mutant counterpart, which were implanted s.c. (s.c.) into nude mice. Two intratumoral (i.t.) injections of 10B-enriched N5-2OH were administered to tumor-bearing mice at 2-hour intervals, after which BNCT was carried out at the Massachusetts Institute of Technology (MIT) Research Reactor. Thirty days after BNCT, mice bearing TK1(+) L929 tumors had a 15x reduction in tumor volume compared with TK1(-) controls. Based on these favorable results, BNCT studies were then initiated in rats bearing intracerebral (i.c.) RG2 gliomas, after i.c. administration of N5-2OH by Alzet osmotic pumps, either alone or in combination with i.v. (i.v.) boronophenylalanine (BPA), a drug that has been used clinically. The mean survival times (MSTs) of RG2 glioma bearing rats were 45.6 ± 7.2 days, 35.0 ± 3.3days, and 52.9 ± 8.9 days, respectively, for animals that received N5-2OH, BPA, or both. The differences between the survival plots of rats that received N5-2OH and BPA alone were highly significant (P = 0.0003). These data provide proof-of-principle that a 3CTA can function as a boron delivery agent for NCT. Further studies are planned to design and synthesize 3CTAs with enhanced chemical and biological properties, and increased therapeutic efficacy.

Original languageEnglish (US)
Pages (from-to)17493-17497
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number45
DOIs
StatePublished - Nov 11 2008

Keywords

  • 3-carboranyl thymidine analogues

ASJC Scopus subject areas

  • General

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    Barth, R. F., Yang, W., Wu, G., Swindall, M., Byun, Y., Narayanasamy, S., Tjarks, W., Tordoff, K., Moeschberger, M. L., Eriksson, S., Binns, P. J., & Riley, K. J. (2008). Thymidine kinase 1 as a molecular target for boron neutron capture therapy of brain tumors. Proceedings of the National Academy of Sciences of the United States of America, 105(45), 17493-17497. https://doi.org/10.1073/pnas.0809569105