[Glutathione and cisplatin resistance in head and neck cancer].
Since glutathione is considered to be an important mediator of cancer cell resistance to cisplatin-based chemotherapy, we investigated glutathione in head and neck cancer by both laboratory and clinical investigations.


METHODS
Intracellular glutathione concentration was measured in 7 different cell lines that originated from head and neck cancer and was correlated to their IC50 to cisplatin. Expression of gamma-glutamyl cysteine (gamma-GCS) mRNA was assessed by in situ hybridization and gamma-glutamyl transpeptidase (GGT) expression was assessed with immnunohistochemistry of 56 biopsy specimens from 51 clinical cases. Both these enzymes are important for maintenance of intracellular glutathione concentration.


RESULTS
Intracellular glutathione concentration was strongly correlated with cisplatin IC50 (R2 = 0.814, P = 0.0012), suggesting that glutathione plays a major role in cisplatin resistance in head and neck cancer. High gamma-GCS expression was observed in 27 out of 47 specimens (57%), but the response rate to chemotherapy (63%) in the high expression group was not significantly different to the low expression group (P = 0.20). High GGT expression was observed in 32 out of 53 specimens (60%), but the response rate in the high GGT group was not significantly different to that of the GGT group.


CONCLUSIONS
Although intracellular glutathione plays an important role in resistance to cisplatin in head and cancer cell lines, we failed to prove that two enzymes that contribute to the maintenance of intracellular glutathione concentration are predictive factors for the response to cisplatin-based chemotherapy. Since clinical cases are further complicated by interactions of the immune system, involvement of a variety of genes related to oncogenesis, and accompanying drugs such as 5FU, it is very difficult to determine a single factor to predict the response to cisplatin. More precise analysis is necessary to determine how head and neck cancer resists cisplatin.
Nishimura
T
T
Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Kanazawa University.
Shiga
H
H
Wakisaka
N
N
Furukawa
M
M
D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000502:physiology*; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D014407:Tumor Cells, Cultured; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D005723:gamma-Glutamyltransferase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D002945:Cisplatin