Gamma-glutamyl transpeptidase accelerates tumor growth and increases the resistance of tumors to cisplatin in vivo.
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.
Hanigan
M H
MH
Department of Cell Biology, University of Virginia, Charlottesville 22908, USA. mhh8b@virginia.edu
Gallagher
B C
BC
Townsend
D M
DM
Gabarra
V
V
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002945:Cisplatin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D003470:Culture Media; D003545:Cysteine / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced / Q000201:enzymology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D005723:gamma-Glutamyltransferase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D000970:Antineoplastic Agents; D003470:Culture Media; D011993:Recombinant Fusion Proteins; D005723:gamma-Glutamyltransferase; D005978:Glutathione; D003545:Cysteine; D002945:Cisplatin