Premium
γ‐Glutamyl transpeptidase‐dependent mutagenicity and cytotoxicity of γ‐glutamyl derivatives: A model for biochemical targeting of chemotherapeutic agents
Author(s) -
Keren Ronit,
Stark AvishayAbraham
Publication year - 1998
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/(sici)1098-2280(1998)32:4<377::aid-em12>3.0.co;2-1
Subject(s) - cytotoxicity , phenylhydrazine , chemistry , biochemistry , gamma glutamyltransferase , enzyme , hep g2 , pharmacology , biology , in vitro , medicinal chemistry
Many carcinomas in humans are rich in γ‐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 γ‐glutamyl derivatives. Chemical conversion of phenylhydrazine (PH) and biochemical modification of daunomycin (DM) into their γ‐glutamyl derivatives γ‐glutamyl phenylhydrazine (GGPH) and γ‐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 γ‐glutamyl‐ p ‐nitroanilide (GGPNA) was not toxic or mutagenic. Mutagenicity and/or cytotoxicity of these γ‐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 γ‐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 γ‐glutamylation is a feasible method for biochemical targeting of drugs containing a primary amino group to GGT‐rich tumors. Environ. Mol. Mutagen. 32:377–386, 1998 © 1998 Wiley‐Liss, Inc.