Elevation of glutathione and related enzyme activities in high-grade and metastatic extremity soft tissue sarcoma

Background: Glutathione is a free radical scavenger implicated in the chemoresistance of certain tumors. As treatment with chemotherapy has added little to improved survival in adult soft tissue sarcoma and little is known concerning the mechanisms of chemoresistance in sarcoma, we studied concentrations of glutathione (nmol/mg protein) and activities of-glutamylcysteine synthetase (GCS; nmol/mg protein/h) and-glutamyl transpeptidase (GGTP; U/mg protein) in extremity soft tissue sarcoma. Methods and Results: Tumor specimens (n=65) were frozen in liquid nitrogen at the time of resection. Fourteen low-grade tumors, 40 high-grade tumors, and 11 pulmonary metastases were analyzed. Glutathione concentrations and GGTP activity were significantly lower in low-grade (3.97±0.7 nmol/mg protein and 1.07±0.2 U/mg protein) than in high-grade (8.98±1.2 nmol/mg protein, p<0.001; 2.10±0.4 U/mg protein, p<0.002) tumors and pulmonary metastases (10.05±1.8 nmol/mg protein, p<0.008; 3.14±2.8 U/mg protein, p<0.04). While GCS activity was lower in low-grade (0.81±0.3 nmol/mg protein/h) than high-grade (1.49±0.5 nmol/mg protein/h) tumors and pulmonary metastases (1.03±0.2 nmol/mg protein/h), these differences were not significant. In those patients with a high-grade tumor presenting with a local recurrence, glutathione levels were higher in those patients who had received preoperative doxorubicin-based chemotherapy (9.25±1.7 nmol/mg protein; n=7) than in those who had no preoperative chemotherapy (4.71±3.1 nmol/mg protein; n=4, p=0.08). Conclusions: In extremity soft tissue sarcoma, glutathione concentration and GGTP activity are significantly elevated in patients with high-grade and metastatic sarcomas. In addition, there is a trend for increased glutathione levels in tumors previously exposed to doxorubicin-based chemotherapy. Glutathione may play a role in soft tissue sarcoma chemoresistance.This work was presented at the 49th Annual Cancer Symposium of the Society of Surgical Oncology, Atlanta, GA, U.S.A., March 21–24, 1996.