Thymidylate synthase activity, folates, and glutathione system in head and neck carcinoma and adjacent tissues.
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.
Parise
O
O
Department of Head and Neck Surgery, Institut Gustave-Roussy, Villejuif, France.
Janot
F
F
Luboinski
B
B
Massaad
L
L
Albin
N
N
Toussaint
C
C
Verjus
M A
MA
Bonnay
M
M
Gouyette
A
A
Chabot
G G
GG
D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000737:chemistry* / Q000201:enzymology / Q000473:pathology; D002945:Cisplatin; D004351:Drug Resistance; D005260:Female; D005472:Fluorouracil; D005492:Folic Acid / Q000032:analysis*; D005978:Glutathione / Q000031:analogs & derivatives / Q000032:analysis*; D019803:Glutathione Disulfide; D005982:Glutathione Transferase / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000737:chemistry* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007820:Laryngeal Mucosa / Q000737:chemistry / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009061:Mouth Mucosa / Q000737:chemistry / Q000201:enzymology; D009367:Neoplasm Staging; D011506:Proteins / Q000032:analysis; D013940:Thymidylate Synthase / Q000032:analysis / Q000378:metabolism*
D011506:Proteins; D005492:Folic Acid; D013940:Thymidylate Synthase; D005982:Glutathione Transferase; D005978:Glutathione; D002945:Cisplatin; D005472:Fluorouracil; D019803:Glutathione Disulfide