Related Experiment Videos
Thymidylate synthase activity, folates, and glutathione system in head and neck carcinoma and adjacent tissues
O Parise1, F Janot, B Luboinski
1Department of Head and Neck Surgery, Institut Gustave-Roussy, Villejuif, France.
Background:
Head and neck squamous cell carcinomas (HNSCC) present variable aggressiveness and chemosensitivity. Because the glutathione (GSH) system and thymidylate synthase (TS) are involved in the resistance to the main drugs used in HNSCC (cisplatin and 5-FU), we studied these systems in tumors and normal mucosae.
Methods:
Tumor samples and normal adjacent mucosae were collected from 37 untreated HNSCC patients. GSH and glutathione S-transferase (GST) activity were assayed by spectrophotometry, whereas TS activity and folates were determined by radioassays.
Results:
Mean GSH levels were higher in tumors (15.2 +/- 8.2 nmol/mg protein) than in mucosae (8.3 +/- 4.1 nmol/mg protein) (p = 0.005, paired t test). GST activity was also higher in tumors (394 +/- 194 nmol/min/mg protein) than in mucosae (261 +/- 132 nmol/min/mg protein) (p = 0.0003). TS activity was markedly higher in tumors (9.2 +/- 21.5 pmol/min/mg protein) compared to that of mucosae (0.9 +/- 1.2 pmol/min/mg protein) (p = 0.0001). Folate levels in tumors and mucosae were similar (1.2 +/- 1.1 and 0.8 +/- 0.9 pmol/mg protein, respectively; p = 0.1, NS). In relation to clinical stage and tumor size, a statistical difference was found in GSH and GST values between tumors and mucosae for stage IV and T3/T4. The increase in tumor TS compared to that of mucosae was significant for all clinical stages, tumor sizes, and nodal involvement.
Conclusions:
These data enhance our understanding of the enzymatic systems involved in cisplatin and 5-fluorouracil (5-FU) resistance in HNSCC and normal mucosae and may help to elucidate tumor behavior and interpatient differences in drug sensitivity.
Insights
Head and neck squamous cell carcinoma (HNSCC) tumors show higher glutathione (GSH) system and thymidylate synthase (TS) activity than normal tissues. These findings offer insights into drug resistance mechanisms for cisplatin and 5-fluorouracil (5-FU) in HNSCC patients.
Area of Science:
- Biochemistry of cancer
- Molecular oncology
- Drug resistance mechanisms
Background:
- Head and neck squamous cell carcinomas (HNSCC) exhibit variable clinical aggressiveness and chemosensitivity.
- The glutathione (GSH) system and thymidylate synthase (TS) are implicated in resistance to key HNSCC chemotherapeutics like cisplatin and 5-fluorouracil (5-FU).
Purpose of the Study:
- To investigate and compare the activity of the GSH system and TS in HNSCC tumors versus adjacent normal mucosa.
- To correlate these enzymatic activities with clinical parameters of HNSCC.
Main Methods:
- Spectrophotometric assays for glutathione (GSH) and glutathione S-transferase (GST) activity.
- Radioassays for thymidylate synthase (TS) activity and folate levels.
- Analysis of tumor and matched normal mucosa samples from 37 untreated HNSCC patients.
Main Results:
- Tumors demonstrated significantly higher mean GSH levels (15.2 vs. 8.3 nmol/mg protein) and GST activity (394 vs. 261 nmol/min/mg protein) compared to normal mucosa.
- TS activity was markedly elevated in tumors (9.2 vs. 0.9 pmol/min/mg protein) across all clinical stages, tumor sizes, and nodal involvement.
- Folate levels did not differ significantly between tumor and normal mucosa.
Conclusions:
- Elevated GSH, GST, and TS activities in HNSCC tumors contribute to understanding cisplatin and 5-FU resistance.
- These findings may aid in predicting tumor behavior and interpatient variability in drug sensitivity for HNSCC.