Gamma-glutamyl transpeptidase accelerates tumor growth and increases the resistance of tumors to cisplatin in vivo - PubMed (original) (raw)

Comparative Study

Gamma-glutamyl transpeptidase accelerates tumor growth and increases the resistance of tumors to cisplatin in vivo

M H Hanigan et al. Carcinogenesis. 1999 Apr.

Abstract

We have shown previously that gamma-glutamyl transpeptidase (GGT) activity is essential for the nephrotoxicity of cisplatin. In this study we asked whether GGT activity was necessary for the antitumor activity of cisplatin. GGT was transfected into PC3 cells, a human prostate tumor cell line. Two independent GGT-positive cell lines were isolated and characterized. GGT cleaves extracellular glutathione providing the cells with access to additional cysteine. Expression of GGT had no effect on the growth rate of the cells in vitro where the culture medium contains high levels of cysteine. However, when the cells were injected into nude mice the GGT-positive tumors grew at more than twice the rate of the GGT-negative tumors. Weekly treatment with cisplatin was toxic to both GGT-positive and -negative tumors. The GGT-positive tumors were significantly more resistant to the toxicity of cisplatin than the GGT-negative tumors. Therefore, expression of GGT is required for the nephrotoxicity of cisplatin, but diminishes the tumor toxicity of the drug. These results indicate that the nephrotoxicity and the tumor toxicity of cisplatin are via two distinct pathways.

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Figures

Fig. 1.

Fig. 1.

Growth of GGT-positive and -negative PC3 cells in vitro and in vivo. Growth in vitro of GGT-positive, PC3 cells (+), GGT-negative, PC3 cells (○) and parental PC3 cells (△) in experiment 1 (A) and experiment 2 (B). Growth of the same PC3 GGT-positive cells (●) and GGT-negative cells (s) when injected into nude mice, experiment 1 (C); experiment 2 (D).

Fig. 2.

Fig. 2.

Weight of mice during treatment with cisplatin. Mice bearing GGT-positive, PC3 tumors (closed symbols) and GGT-negative PC3 tumors (open symbols) were weighed weekly prior to injection with saline (circles), 2.5 mg/kg cisplatin (squares) or 5.0 mg/kg cisplatin (triangles) in experiment 1 (A) and experiment 2 (B).

Fig. 3.

Fig. 3.

Immunohistochemical staining of tumors derived from PC3/GGT1 cells (A) and PC3/GGT2 cells (B). Tumors were stained with GGT129, an antibody directed against a 20 amino acid sequence in the human GGT protein. Antibody staining in the controls, PC3/C1 and PC3/C2 derived tumors, was negative (data not shown).

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