The relationship of the human glutathione S-transferase P1 polymorphism and chemotherapeutic sensitivity in head and neck squamous carcinoma.
GSTP1, which encodes GSTPi, has a polymorphic site at codon 105 (exon 5), where an adenosine-to-guanine (A-G) transition causes an isoleucine-to-valine substitution (I105V). Recent studies have found that subjects with the valine allele display a significantly lower enzyme activity and less effective capability of detoxification. We hypothesized that head and neck squamous cell carcinoma (HNSCC) might respond differently to chemotherapeutic agents, especially cisplatin (CDDP) because of the presence of GSTP1 I105V polymorphism. Seventeen types of HNSCC cell lines were investigated with the MTT method, western blot, RT-PCR and direct sequence to examine the relationship between the sensitivity to CDDP and expression of GSTPi. There was a significant degree of difference in cell death among each cell line in the sensitivity test with CDDP, however, we did not find differences in the band density of the protein and mRNA expression levels of GSTPi. In the direct sequence examination we detected 4 subjects heterozygous of polymorphism GSTP1. The frequency was 23.5% in the 17 cell lines examined, and all 4 subjects showed a good response to CDDP treatment. A heterozygous polymorphism might alter the function of the GSTPi due to significantly lower enzyme activity and less effective capability of detoxification. Two other subjects which showed a good response to CDDP treatment did not show any polymorphism. These results indicated that there is another locus that reduces GSTPi activity, and that the mechanisms of CDDP resistance was multifactorial. Further study is required to conclude whether the GSTP1 I105V polymorphism might be useful as a predictive marker for multi-drug resistance.
Kimura
Shinobu
S
Department Otorhinolaryngology, Yokohama City University School of Medicine, Kanazawaku, Yokohama City, Kanagawa prefecture 236-0023, Japan. skimura@med.yokohama-cu.ac.jp
Imagawa
Yukari
Y
Satake
Kenichi
K
Tsukuda
Mamoru
M
D000483:Alleles; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D005091:Exons; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D020128:Inhibitory Concentration 50; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014633:Valine / Q000235:genetics
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D013778:Tetrazolium Salts; D013844:Thiazoles; D005982:Glutathione Transferase; C022616:thiazolyl blue; D014633:Valine; D002945:Cisplatin