Role of O6-methylguanine-DNA methyltransferase and effect of O6-benzylguanine on the anti-tumor activity of cis-diaminedichloroplatinum(II) in oral cancer cell lines.
The DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) modulates the effectiveness of alkylating agents. However, the relationship between MGMT and the sensitivities to other agents has not been explored. In the present study, the association between MGMT expression and the cellular sensitivity to the platinum agent, CDDP was examined in four human oral cancer cell lines. CDDP depleted MGMT protein and mRNA levels in all four cell lines. Two cell lines with low MGMT expression were sensitive to an alkylating agent, N-methyl-N'-nitro-N-nitrosoguanidine and CDDP, whereas two other cell lines with high MGMT expression were resistant to both agents. Furthermore, the addition of the MGMT inhibitor, O6-benzylguanine (O6-BG), invariably enhanced CDDP sensitivity. CDDP depleted MGMT expression, and CDDP sensitivity was enhanced by O6-BG. These results provide valuable information about the relationship between MGMT expression and CDDP sensitivity in oral cancer chemotherapy.
Maki
Yu
Y
Department of Oral and Maxillofacial Radiology, Field of Tumor Biology, Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Okayama 700-8525, Japan.
Murakami
Jun
J
Asaumi
Jun-ichi
J
Tsujigiwa
Hidetsugu
H
Nagatsuka
Hitoshi
H
Kokeguchi
Susumu
S
Fukui
Kazuhiro
K
Kawai
Noriko
N
Yanagi
Yoshinobu
Y
Kuroda
Masahiro
M
Tanaka
Noriaki
N
Matsubara
Nagahide
N
Kishi
Kanji
K
D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D004260:DNA Repair; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D008769:Methylnitronitrosoguanidine / Q000627:therapeutic use; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000187:drug effects / Q000378:metabolism*; D043823:Taxoids / Q000008:administration & dosage
D000970:Antineoplastic Agents; D043823:Taxoids; C064976:O(6)-benzylguanine; D008769:Methylnitronitrosoguanidine; D000077143:Docetaxel; D006147:Guanine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002945:Cisplatin