Potentiation of cytotoxicity by 3-aminobenzamide in DNA repair-deficient human tumor cell lines following exposure to methylating agents or anti-neoplastic drugs.
We studied the potentiation by 3-aminobenzamide (3AB) of killing of nine human cell lines exposed to alkylating agents. Cell lines included normal, transformed and DNA repair-proficient and -deficient phenotypes. 3AB potentiated cell killing by the methylating agents methylmethanesulfonate (MMS) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in all lines tested. The degree of potentiation ranged from 1.7- to 3.8-fold, based on the LD99. The average potentiation observed with MMS (2.7-fold) was greater than with MNNG (2.2-fold). On average the potentiation of MMS and MNNG killing of repair-deficient Mer- lines (2.4-fold) was similar to that of repair-proficient Mer+ lines. The degree of 3AB potentiation of MNNG killing (2.0-fold) was similar in Mer+ Rem- lines and in Mer+ Rem+ lines. Mer+ Rem+, Mer+ Rem-, Mer- Rem+, and Mer- Rem- strains all appeared proficient in a 3AB-sensitive DNA repair pathway. Within experimental error, 20 mM 3AB did not inhibit the removal of the MNNG-induced methylpurines 7-methylguanine, O6-methylguanine and 3-methyladenine from the DNA of repair-proficient Mer+ Rem+ HT29 cells, consistent with evidence that 3AB inhibits the ligation step of excision repair. 3AB potentiated cell killing by the bifunctional alkylating agents 1-(2-chlorethyl)-1-nitrosourea or busulfan, two anti-neoplastic drugs, by only 0.9- to 1.5-fold. These drugs therefore produce DNA damage which is not efficiently repaired by the pathways that repair methylated bases.
Babich
M A
MA
Laboratory of Molecular Carcinogenesis, National Cancer Institute, Bethesda, MD.
Day
R S
RS
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D002066:Busulfan / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D004260:DNA Repair; D004357:Drug Synergism; D005038:Ethylnitrosourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008741:Methyl Methanesulfonate / Q000494:pharmacology*; D008745:Methylation; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D001549:Benzamides; D008769:Methylnitronitrosoguanidine; C017139:1-(2-chloroethyl)-1-nitrosourea; C025160:3-aminobenzamide; D008741:Methyl Methanesulfonate; D002066:Busulfan; D005038:Ethylnitrosourea