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[Cancer Research 63, 6008-6015, September 15, 2003]
© 2003 American Association for Cancer Research

Regular Articles

Radiosensitization and DNA Repair Inhibition by the Combined Use of Novel Inhibitors of DNA-dependent Protein Kinase and Poly(ADP-Ribose) Polymerase-11

Stephany J. Veuger, Nicola J. Curtin, Caroline J. Richardson, Graeme C. M. Smith and Barbara W. Durkacz2

Northern Institute for Cancer Research, Medical School, University of Newcastle, Newcastle upon Tyne NE2 4HH [S. J. V., N. J. C., B. W. D.], and KuDOS Pharmaceuticals, Cambridge Science Park, Cambridge CB4 4WG [C. J. R., G. C. M. S.], United Kingdom

The DNA repair enzymes, DNA-dependent protein kinase (DNA-PK) and poly(ADP-ribose) polymerase-1 (PARP-1), are key determinants of radio- and chemo-resistance. We have developed and evaluated novel specific inhibitors of DNA-PK (NU7026) and PARP-1 (AG14361) for use in anticancer therapy. PARP-1- and DNA-PK-deficient cell lines were 4-fold more sensitive to ionizing radiation (IR) alone, and showed reduced potentially lethal damage recovery (PLDR) in G0 cells, compared with their proficient counterparts. NU7026 (10 µM) potentiated IR cytotoxicity [potentiation factor at 90% cell kill (PF90) = 1.51 ± 0.04] in exponentially growing DNA-PK proficient but not deficient cells. Similarly, AG14361 (0.4 µM) potentiated IR in PARP-1+/+ (PF90 = 1.37 ± 0.03) but not PARP-1-/- cells. When NU7026 and AG14361 were used in combination, their potentiating effects were additive (e.g., PF90 = 2.81 ± 0.19 in PARP-1+/+ cells). Both inhibitors alone reduced PLDR ~3-fold in the proficient cell lines. Furthermore, the inhibitor combination completely abolished PLDR. IR-induced DNA double strand break (DNA DSB) repair was inhibited by both NU7026 and AG14361, and use of the inhibitor combination prevented 90% of DNA DSB rejoining, even 24-h postirradiation. Thus, there was a correlation between the ability of the inhibitors to prevent IR-induced DNA DSB repair and their ability to potentiate cytotoxicity. Thus, individually, or in combination, the DNA-PK and PARP-1 inhibitors act as potent radiosensitizers and show potential as tools for anticancer therapeutic intervention.




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