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γ‐glutamyltranspeptidase expression regulates the growth‐inhibitory activity of the anti‐tumor prodrug γ‐L‐glutaminyl‐4‐hydroxy‐3‐iodobenzene
Author(s) -
Prezioso Joseph A.,
Hughey Rebecca P.,
Wang Nu,
Damodaran Kalyani M.,
Bloomer William D.
Publication year - 1994
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910560620
Subject(s) - chinese hamster ovary cell , microbiology and biotechnology , biochemistry , chemistry , cytotoxic t cell , transfection , biology , in vitro , receptor , gene
γ‐L‐glutaminyl‐4‐hydroxy‐3‐iodobenzene (I‐GHB), a novel iodinated analog of γ‐L‐glutaminyl‐4‐hydrpxybenzene (GHB), demonstrates greater anti‐tumor activity in human and in murine melanoma cell lines. These phenolic amides are substrates for γ‐glutamyltranspeptidase (GGTP; E.G. 2.3.2.2), a cell‐membrane‐associated ecto‐enzyme which is elevated in a number of tumor systems. We now present data to show that the growth‐inhibitory activity of I‐GHB and GHB may be mediated via GGTP‐catalyzed reactions. The growth‐inhibitory activity of I‐GHB and GHB in pigmented B16‐BL6 melanoma cells was blocked significantly by rabbit anti‐rat GGTP polyclonal antibodies. The combination of L‐serine and sodium borate, a specific transition‐state inhibitor of GGTP, as well as acivicin, a glutamine antagonist and irreversible GGTP inhibitor, inhibited the killing of BL6 cells by GHB and I‐GHB. To further define the role of GGTP expression in the regulation of phenolic amide cytotoxicity, GGTP‐negative Chinese hamster ovary cells (CHO‐KI) were transfected with a functional rat renal cDNA representing the full‐length GGTP transcript. I‐GHB and GHB were significantly more cytotoxic in GGTP cDNA transfected Chinese hamster ovary (CHO‐KI‐GGTP) cells than in non‐transfected CHO‐KI cells. The combination of L‐serine and sodium borate blocked the cytotoxic activity of these pro‐drugs and also inhibited GGTP‐catalyzed formation of polymerized products from these phenolic amides in intact BL6 melanoma and CHO‐KI‐GGTP cells. Furthermore, melanin formation from GHB was not observed in non‐transfected CHO‐KI cells lacking GGTP expression. The combined data strongly suggest that GGTP‐catalyzed hydrolysis of the anti‐tumor pro‐drugs I‐GHB and GHB to 4‐aminophenols mediates the expression of antitumor activity.