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Thymidine kinase 1 as a molecular target for boron neutron capture therapy of brain tumors.
Barth, Rolf F; Yang, Weilian; Wu, Gong; Swindall, Michele; Byun, Youngjoo; Narayanasamy, Sureshbabu; Tjarks, Werner; Tordoff, Kevin; Moeschberger, Melvin L; Eriksson, Staffan; Binns, Peter J; Riley, Kent J.
Afiliação
  • Barth RF; Department of Pathology, Division of Biostatistics, Ohio State University, Columbus, OH 43210, USA. rolf.barth@osumc.edu
Proc Natl Acad Sci U S A ; 105(45): 17493-7, 2008 Nov 11.
Article em En | MEDLINE | ID: mdl-18981415
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 (10)B-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 +/- 3.3 days, 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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Timidina / Timidina Quinase / Neoplasias Encefálicas / Compostos de Boro / Terapia por Captura de Nêutron de Boro Limite: Animals Idioma: En Ano de publicação: 2008 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Timidina / Timidina Quinase / Neoplasias Encefálicas / Compostos de Boro / Terapia por Captura de Nêutron de Boro Limite: Animals Idioma: En Ano de publicação: 2008 Tipo de documento: Article