title: Gamma-glutamyl transpeptidase-dependent mutagenicity and cytotoxicity of gamma-glutamyl derivatives: a model for biochemical targeting of chemotherapeutic agents.
abstract: Many carcinomas in humans are rich in gamma-glutamyl transpeptidase (GGT), a plasma membrane enzyme that reacts with extracellular substrates. Thus, biochemical targeting of chemotherapeutic agents may be achieved by converting anticancer drugs into their gamma-glutamyl derivatives. Chemical conversion of phenylhydrazine (PH) and biochemical modification of daunomycin (DM) into their gamma-glutamyl derivatives gamma-glutamyl phenylhydrazine (GGPH) and gamma-glutamyl DM (GGDM) resulted in the abolishment of their mutagenicity and cytotoxicity, as judged by decreased viability and increased mutant yields in cultures of several Salmonella Ames strains. Commercial gamma-glutamyl-p-nitroanilide (GGPNA) was not toxic or mutagenic. Mutagenicity and/or cytotoxicity of these gamma-glutamyl derivatives were restored upon reaction with GGT, with concomitant release of PH, and p-nitroaniline (PNA). The GGT-dependent release of DM from GGDM was demonstrated by thin layer chromatography (TLC), spectral analysis, and specific mutagenicity. Mutagenicity and/or cytotoxicity of gamma-glutamyl derivatives increased in the presence of glycylglycine, a GGT activator, and decreased in the presence of serine-borate, a GGT inhibitor. GGDM retained considerable DNA binding capacity. Its inability to kill and mutagenize was due to altered transport properties. The results are compatible with the notion that gamma-glutamylation is a feasible method for biochemical targeting of drugs containing a primary amino group to GGT-rich tumors.
authors.affiliation: Department of Biochemistry, Tel-Aviv University, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Keren
authors.forename: A A
authors.initials: AA
authors.lastname: Stark
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001711:Biotransformation; D004247:DNA / Q000187:drug effects; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000633:toxicity; D005973:Glutamine / Q000031:analogs & derivatives / Q000633:toxicity*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D005723:gamma-Glutamyltransferase / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D009153:Mutagens; D005973:Glutamine; D004247:DNA; D005723:gamma-Glutamyltransferase; D003630:Daunorubicin