Evaluation of TK1 targeting carboranyl thymidine analogs as potential delivery agents for neutron capture therapy of brain tumors

Abstract

In this report we describe studies with N5-2OH, a carboranyl thymidine analog (CTA), which is a substrate for thymidine kinase 1 (TK1), using the F98 rat glioma model. In vivo BNCT studies have demonstrated that intracerebral (i.c.) osmotic pump infusion of N5-2OH yielded survival data equivalent to those obtained with i.v. administration of boronophenylalanine (BPA). The combination of N5-2OH and BPA resulted in a modest increase in MST of F98 glioma bearing rats compared to a statistically significant increase with the RG2 glioma model, as has been previously reported by us (Barth et al., 2008). This had lead us to synthesize a second generation of CTAs that have improved in vitro enzyme kinetics and in vivo tumor uptake (Agarwal et al., 2015).

Keywords: BNCT; Carboranyl thymidine analogs; F98 rat glioma; N5-2OH.

Fig. 1

Chemical structure of N5-2OH.

Fig. 2

Western blot analysis of TK1 protein expression in F98W, TK1⁻ L929, and TK1⁺ L929 cells.

Fig. 3

A: Kaplan-Meier survival plots for F98 glioma bearing rats. Survival times have been plotted for untreated animals (●), irradiated controls (○), and animals that received i.v. BPA (◆) or N5-2OH either alone (▲) or in combination with BPA (◇). Fig. 3B: Cox survival plots for F98 glioma bearing rats. Survival times have been plotted for untreated animals (●), irradiated controls (○), and animals that received i.v. BPA (◆) or N5-2OH either alone (▲) or in combination with BPA (◇). It should be noted that Cox's method performs a simultaneous fit of the survival curves using all the data points with a partial likelihood approach. Therefore, the number of data points in each curve includes all of the death times, rather than those animals in a specific group.