title: Thymidine kinase 1 as a molecular target for boron neutron capture therapy of brain tumors.
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.
authors.affiliation: Department of Pathology, Division of Biostatistics, Ohio State University, Columbus, OH 43210, USA. rolf.barth@osumc.edu
authors.forename: Rolf F
authors.initials: RF
authors.lastname: Barth
authors.forename: Weilian
authors.initials: W
authors.lastname: Yang
authors.forename: Gong
authors.initials: G
authors.lastname: Wu
authors.forename: Michele
authors.initials: M
authors.lastname: Swindall
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Byun
authors.forename: Sureshbabu
authors.initials: S
authors.lastname: Narayanasamy
authors.forename: Werner
authors.initials: W
authors.lastname: Tjarks
authors.forename: Kevin
authors.initials: K
authors.lastname: Tordoff
authors.forename: Melvin L
authors.initials: ML
authors.lastname: Moeschberger
authors.forename: Staffan
authors.initials: S
authors.lastname: Eriksson
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Binns
authors.forename: Kent J
authors.initials: KJ
authors.lastname: Riley
mesh_terms: D000818:Animals; D001896:Boron Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D016754:Boron Neutron Capture Therapy / Q000379:methods*; D001932:Brain Neoplasms / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D051381:Rats; D013936:Thymidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D013937:Thymidine Kinase / Q000378:metabolism*
chemical_list: C514063:3-(5-(2-(2,3-dihydroxyprop-1-yl)-o-carboran-1-yl)pentan-1-yl)thymidine; D001896:Boron Compounds; D013937:Thymidine Kinase; C092717:thymidine kinase 1; D013936:Thymidine