γ-glutamyltranspeptidase expression regulates the growth-inhibitory activity of the anti-tumor prodrug γ-L-glutaminyl-4-hydroxy-3-iodobenzene
✍ Scribed by Joseph A. Prezioso; Rebecca P. Hughey; Nu Wang; Kalyani M. Damodaran; William D. Bloomer
- Publisher
- John Wiley and Sons
- Year
- 1994
- Tongue
- French
- Weight
- 750 KB
- Volume
- 56
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
y-L-glutaminyl-4-hydroxy-3-iodobenzene (I-GHB), a novel iodinated analog of y-L-glutarninyl-4-hydroxybenzene (GHB), demonstrates greater anti-tumor activity in human and in murine melanoma cell lines. These phenolic amides are substrates for y-glutamyltranspeptidase (GGTP; E.C. 2.3.2.2), a cell-membraneassociated ecto-enzyme which is elevated in a number of tumor systems. We now present data to show that the growthinhibitory 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.