Novel artificial endonucleases inhibit base excision repair and potentiatethe cytotoxicity of DNA-damaging agents on L1210 cells

A series of molecules with apurinic/apyrimidic (AP) endonuclease activity t argeted to abasic sites in DNA, which incorporate an intercalating moiety l inked to a purine base by a polyamino chain and recognize and cleave abasic sites in DNA with high efficiency, has been studied. The aim was first to establish whether these compounds were inhibitors of base excision DNA repa ir, since abasic sites are generated during this process. Using an extensio n of a recently established methodology, two members of this series have be en identified as definite repair inhibitors. Secondly, the potential of usi ng such compounds as sensitizers of alkylating agents has been investigated by determining the cytotoxic activity of these compounds on L1210 cells in culture. A concentration-dependent potentiation of nitrosoureas has been d emonstrated, but interpretation is complicated by the inherent cytotoxic pr operties of the test compounds themselves. Such molecules, however, provide interesting lead compounds for new strategies aimed at enhancing the cytot oxic potential of clinically useful DNA-damaging agents. [(C) 1999 Lippinco tt Williams & Wilkins.]