Thymidine kinase 1 as a molecular target for boron neutron capture therapy of brain tumors
- 11 November 2008
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 105 (45), 17493-17497
- https://doi.org/10.1073/pnas.0809569105
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 B-10-enriched N5-20H 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, BINICT studies were then initiated in rats bearing intracerebral (i.c.) RG2 gliomas, after i.c. administration of N5-20H by Alzet osmotic pumps, either alone or in combination with i.v. (i.v.) boronophenylalanine (BIPA), 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 N5-20H, BIPA, or both. The differences between the survival plots of rats that received N5-20H and BIPA 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.This publication has 29 references indexed in Scilit:
- Molecular Targeting and Treatment of Composite EGFR and EGFRvIII-Positive Gliomas Using Boronated Monoclonal AntibodiesClinical Cancer Research, 2008
- Quantitative subcellular imaging of boron compounds in individual mitotic and interphase human glioblastoma cells with imaging secondary ion mass spectrometry (SIMS)Journal of Microscopy, 2007
- Boron Neutron Capture Therapy in the Treatment of Locally Recurred Head and Neck CancerInternational Journal of Radiation Oncology*Biology*Physics, 2007
- BORON NEUTRON CAPTURE THERAPY FOR MALIGNANT TUMORS RELATED TO MENINGIOMASNeurosurgery, 2007
- Molecular Targeting and Treatment of an Epidermal Growth Factor Receptor–Positive Glioma Using Boronated CetuximabClinical Cancer Research, 2007
- Epidermal Growth Factor Receptor Targeting in CancerSeminars in Oncology, 2006
- Preparation and Biological Evaluation of 10B-Enriched 3-[5-{2-(2,3-Dihydroxyprop-1-yl)-o-carboran-1-yl}pentan-1-yl]thymidine (N5-2OH), a New Boron Delivery Agent for Boron Neutron Capture Therapy of Brain TumorsJournal of Medicinal Chemistry, 2006
- Molecular Targeting and Treatment of EGFRvIII-Positive Gliomas Using Boronated Monoclonal Antibody L8A4Clinical Cancer Research, 2006
- Boron Neutron Capture Therapy of Cancer: Current Status and Future ProspectsClinical Cancer Research, 2005
- Enhanced Delivery of Boronophenylalanine for Neutron Capture Therapy by Means of Intracarotid Injection and Blood-Brain Barrier DisruptionNeurosurgery, 1996