γ-Glutamyl transpeptidase-dependent mutagenicity and cytotoxicity of γ-glutamyl derivatives: A model for biochemical targeting of chemotherapeutic agents
✍ Scribed by Ronit Keren; Avishay-Abraham Stark
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 315 KB
- Volume
- 32
- Category
- Article
- ISSN
- 0893-6692
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✦ Synopsis
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.