Down-regulation of O6-methylguanine-DNA methyltransferase gene expression in gliomas by platinum compounds

Forty-two patients with malignant gliomas that had received two courses of chemotherapy more than 2 months apart were examined. Among these 42 patients, 31 were treated with 1-(4-amino-2-methyl-5-pyrimidynyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU), and 11 were treated with platinum compounds such as cis-platinum (CDDP) or carboplatin (CBDCA), as the first-line chemotherapy. The response rate of the second chemotherapy in the 31 patients treated first with ACNU was significantly lower than that in the 11 patients treated with platinum compounds, regardless of the type of the second chemotherapy (P=0.0292 by Fisher's exact probability test). O(6)-methylguanine-DNA methyltransferase (MGMT) mRNA expression was measured twice by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) using Sybr-Green I in 16 of 42 patients. The relative quantitation value (RQV) of MGMT mRNA normalized to the level of 2-microglobulin decreased after chemotherapy in all 5 patients treated with platinum compound. U373MG and A172 human glioma cells were cultured for 5 days with 1 microM of CDDP or 4 microM of CBDCA. The RQV of MGMT in these cells treated with platinum compounds obviously decreased, and these cells were more sensitive to ACNU than the control cells based on colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Both the clinical findings and laboratory results suggest that platinum compounds may play a role in the down-regulation of MGMT mRNA expression and up-regulation of the sensitivity to ACNU. Platinum compounds may be strong candidates for use as first-line chemotherapeutic agents against malignant gliomas.