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

• Published in: Applied radiation and isotopes Vol. 106; pp. 251 - 255
• Main Authors: Barth, Rolf F., Yang, Weilian, Nakkula, Robin J., Byun, Youngjoo, Tjarks, Werner, Chu Wu, Lai, Binns, Peter J., Riley, Kent J.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-12-2015
• Subjects: Animals; BNCT; Boron Neutron Capture Therapy; Brain Neoplasms - radiotherapy; Carboranyl thymidine analogs; F98 rat glioma; N5-2OH; Rats; Thymidine - administration & dosage; Thymidine - analogs & derivatives; Thymidine Kinase - drug effects; F98 rat glioma; BNCT; Carboranyl thymidine analogs; N5-2OH
• ISSN: 0969-8043; 1872-9800
• DOI: 10.1016/j.apradiso.2015.06.031

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).
•Strong thymidine kinase (TK1) expression in F98 cells was demonstrated by Western blot analysis. Target validation was established using the L929 TK1+ and mutant TK1− cell lines.•In vivo BNCT studies with the F98 glioma model demonstrated that intracerebral Alzet pump infusion of N5-2OH yielded survival data that were equivalent to those obtained with i.v. administration of boronophenylalanine (BPA).•The combination of N5-2OH and BPA resulted in a modest increase (43.5d versus 36.7d) in mean survival time of F98 glioma bearing rats.