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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 45; pp. 17493 - 17497
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11-11-2008; National Acad Sciences
• Subjects: Animals; Biological Sciences; Blood; Boron; Boron Compounds - administration & dosage; Boron Compounds - chemistry; Boron Compounds - metabolism; Boron Compounds - therapeutic use; Boron neutron capture therapy; Boron Neutron Capture Therapy - methods; Brain; Brain neoplasms; Brain Neoplasms - radiotherapy; Cell cycle; Cell growth; Cell Line, Tumor; Cells; Glioma; Kinases; Mice; Mice, Nude; Molecular Structure; Neutron capture therapy; Rats; Rodents; Studies; Thymidine - administration & dosage; Thymidine - analogs & derivatives; Thymidine - chemistry; Thymidine - metabolism; Thymidine - therapeutic use; Thymidine Kinase - metabolism; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0809569105

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.