Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the United States. Because NSCLC is highly chemoresistant, it is usually not treatable. Altered glutathione (GSH) metabolism is thought to be one major mechanism of chemoresistance, and GSH levels are reported to be elevated in NSCLC. The main objective of this study is to delineate the potential mechanisms involved in elevation of tissue GSH, including extraction from the circulation by NSCLC. Twenty consecutive patients with NSCLC were enrolled. At the time of lobectomy, pulmonary artery and vein were identified, and blood flow was measured by an electromagnetic probe. Subsequently, blood samples were drawn from pulmonary artery, the vein draining the tumor-bearing lobe, and a normal lobe. Immediately after lobectomy, tumor and lung specimens were snap frozen. NSCLC tumor specimens had higher levels of GSH compared with lung tissue (20.8 ± 9.4 versus 11.6 ± 3.0 nmol/mg protein, respectively; P < 0.05). The tumor demonstrated higher activity of the enzyme γ-glutamyl transpeptidase, a membrane-bound enzyme involved in transmembrane uptake of GSH, than lung tissue (41.9 ± 26.4 versus 22.4 ± 12.3 units/mg protein, respectivel; P < 0.05). Also, the tumor-bearing lobe showed elevated extraction of GSH and two of its component amino acids compared with lung tissue (GSH uptake: 0.60 ± 0.67 versus 0.20 ± 0.40 µm/min, respectively; P < 0.05). NSCLC tumors are able to extract circulating GSH and its constituent amino acids to synthesize intracellular GSH. Increased activity of γ-glutamyl transpeptidase may be one mechanism underlying increased GSH uptake by NSCLC.

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