|Budget Amount *help
¥6,300,000 (Direct Cost : ¥6,300,000)
Fiscal Year 1996 : ¥1,500,000 (Direct Cost : ¥1,500,000)
Fiscal Year 1995 : ¥4,800,000 (Direct Cost : ¥4,800,000)
Drug resistance has been a major problem in the clinical failure of chemotherapeutic chloroethylnitrosoureas (CENUs) for high-grade gliomas. O^6-Methylguanine-DNA methyltransferase (MGMT) plays a key role in cellular resistance to CENUs by accepting CENU-forming fatal adducts. CENUs should be limited to sensitive gliomas on the basis of MGMT activity. Inactivation of MGMT activity by exogenous O^6-alkylguanine derivatives, substrates of MGMT,is another strategy to overcome MGMT-related resistance.
We measured the levels of MGMT mRNA expression in human brain tumors, and studied the significance of MGMT mRNA levels in CENU chemotherapy. High-grade gliomas had significantly lower levels of MGMT mRNA than did low-grade gliomas and non-glial tumors (P<0.05). Out of 11 patients who received CENU chemotherapy, three had a partial response. All three responders had a low level of MGMT mRNA.The time to tumor progression for six patients with a level lower than the median was small but significa
ntly longer than that for five patients with a higher level (P<0.05).
O^6-Alkylguanine derivatives tested as an MGMT inactivator were O^6- (4-, 3-, and 2-fluorobenzyl) guanines, O^6- (4,3-, and 2-trifluoromethylbenzyl) guanines, and O^6- (4-, 3-, and 2-pyridylmethyl) guanines. Among these, compounds with an adduct at 4- or 3-position showed a strong MGMT depletion activity, whereas compounds with an adduct at 2-position were inactive. There was a good relationship (r=-0.856, p<0.001) between the MGMT depletion activity of O^6-alkylguanines and their potentiation activity of cytotoxicity of ACNU,a CENU.
These results indicate that a fraction of brain tumors have a low expression of MGMT mRNA,and that the level of MGMT mRNA is a useful indicator of effectiveness in selective CENU chemotherapy. The position of benzyl groups is important for the interaction of O^6-alkylguanine derivatives with MGMT to result in the inactivation of MGMT.Potent MGMT inactivators sensitize tumor cells to CENU chemotherapy. Less