Novel artificial endonucleases inhibit base excision repair and potentiate the cytotoxicity of DNA-damaging agents on L1210 cells.
A series of molecules with apurinic/apyrimidic (AP) endonuclease activity targeted to abasic sites in DNA, which incorporate an intercalating moiety linked 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 repair, since abasic sites are generated during this process. Using an extension of a recently established methodology, two members of this series have been identified as definite repair inhibitors. Secondly, the potential of using 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 demonstrated, but interpretation is complicated by the inherent cytotoxic properties of the test compounds themselves. Such molecules, however, provide interesting lead compounds for new strategies aimed at enhancing the cytotoxic potential of clinically useful DNA-damaging agents.
Barret
J M
JM
Division de Cancérologie Expérimentale, Institut de Recherches Pierre Fabre, Castres, France. jean_marc.barret@pierre-fabre.com
Etiévant
C
C
Fahy
J
J
Lhomme
J
J
Hill
B T
BT
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D020029:Base Pairing; D002330:Carmustine / Q000494:pharmacology; D004260:DNA Repair / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004720:Endonucleases / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000235:genetics; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D051379:Mice; D014176:Protein Biosynthesis; D011506:Proteins / Q000187:drug effects; D012313:RNA / Q000096:biosynthesis / Q000187:drug effects; D013311:Streptozocin / Q000494:pharmacology; D013852:Thiotepa / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D004273:DNA, Neoplasm; D011506:Proteins; D013311:Streptozocin; D012313:RNA; D013852:Thiotepa; D008741:Methyl Methanesulfonate; D004720:Endonucleases; D002330:Carmustine