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 15؋ 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.
3-carboranyl thymidine analogues
Boron neutron capture therapy (BNCT) is one of many experimental approaches that has been used to treat patients with glioblastoma multiforme (GBM), the most malignant of all human brain tumors (1, 2). It is a radiotherapeutic modality that is based on the selective delivery of nonradioactive boron-10 ( 10 B), followed by irradiation with either low energy thermal or intermediate energy epithermal neutrons to the site of the tumor. Besides GBMs, BNCT has been used to treat patients with recurrent malignant meningiomas (3), either cutaneous primaries or cerebral metastases of melanoma (1), and most recently, patients with recurrent carcinomas of the head and neck (4), and hepatic metastases of colon cancer (5). Interested readers are referred to several recent reviews (1) and monographs relating to various aspects of BNCT (6, 7).A prerequisite for successful BNCT is the selective accumulation of 10 B within tumor cells. To accomplish this, a wide variety of low and high molecular weight boron delivery agents have been designed and synthesized to specifically target malignant cells (8). However, only two agents have been used clinically, a dihydroxyboryl derivative of phenylalanine, referred to as boronphenylalanine (BPA), and an anionic polyhedral boron cluster, sodium borocaptate (BSH). Our most recent studies have focused on two specific molecular...