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Elevation of glutathione and related enzyme activities in high-grade and metastatic extremity soft tissue sarcoma
S N Hochwald1, D M Rose, M F Brennan
1Surgical Metabolism Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
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 gamma-glutamylcysteine synthetase (GCS; nmol/mg protein/h) and gamma-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.
Insights
Glutathione levels and gamma-glutamyl transpeptidase activity are higher in high-grade and metastatic soft tissue sarcomas. These findings suggest glutathione
Area of Science:
- Oncology
- Biochemistry
Background:
- Glutathione (GSH) is a key antioxidant and free radical scavenger.
- Chemoresistance is a significant challenge in treating adult soft tissue sarcoma (STS).
- Mechanisms of chemoresistance in STS are not fully understood.
Purpose of the Study:
- To investigate glutathione concentrations and the activities of gamma-glutamylcysteine synthetase (GCS) and gamma-glutamyl transpeptidase (GGTP) in extremity soft tissue sarcoma.
- To explore the relationship between these markers and tumor grade, metastatic potential, and response to chemotherapy.
Main Methods:
- Analysis of tumor specimens (n=65) from patients with extremity soft tissue sarcoma.
- Measurement of glutathione concentrations (nmol/mg protein).
- Assay of gamma-glutamylcysteine synthetase (GCS) and gamma-glutamyl transpeptidase (GGTP) activities.
Main Results:
- Significantly higher glutathione concentrations and GGTP activity were observed in high-grade tumors and pulmonary metastases compared to low-grade tumors.
- While GCS activity was lower in low-grade tumors, the difference was not statistically significant.
- A trend towards increased glutathione levels was noted in high-grade tumors previously treated with doxorubicin-based chemotherapy.
Conclusions:
- Elevated glutathione concentration and GGTP activity are associated with high-grade and metastatic extremity soft tissue sarcoma.
- Glutathione may play a crucial role in the chemoresistance of soft tissue sarcomas.
- Further research is warranted to explore therapeutic strategies targeting glutathione pathways in STS.