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

摘要: The purpose of the present study was to evaluate effectiveness 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) brain tumors using RG2 rat glioma model. Target validation established 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 10B-enriched N5–2OH administered tumor-bearing mice at 2-hour intervals, after BNCT carried out Massachusetts Institute Technology (MIT) Research Reactor. Thirty days BNCT, bearing TK1(+) had 15× reduction in tumor volume compared with controls. Based on these favorable results, studies then initiated rats intracerebral (i.c.) gliomas, i.c. administration by Alzet osmotic pumps, either alone or combination i.v. (i.v.) boronophenylalanine (BPA), drug that has been used clinically. mean survival times (MSTs) 45.6 ± 7.2 days, 35.0 3.3days, 52.9 8.9 respectively, animals received BPA, both. differences between plots BPA highly significant (P = 0.0003). These data provide proof-of-principle 3CTA can function as delivery agent NCT. Further are planned design synthesize 3CTAs enhanced chemical biological properties, increased therapeutic efficacy.