CADD-19. PAM-OBG: A MAOB-SPECIFIC PRODRUG INHIBITOR OF O6-METHYLGUANINE DNA METHYLTRANSFERASE (MGMT) THAT SENSITIZES GMB TO BCNU/CCNU

摘要

INTRODUCTIONMGMT gene methylation status indicate the levels of the DNA repair enzyme O⁶-methylguanine DNA methyltransferase (MGMT) in glioma. MGMT repairs the DNA lesions caused by classical alkylating agents TMZ, BCNU and CCNU. Systemic inhibition of MGMT using the inhibitor O⁶-methylguanine (OBG) in GBM patients, prior to chemotherapy with TMZ or BCNU has failed due to toxicity toward bone marrow. We have shown that the enzyme monoamine oxidase B (MAOB) is upregulated in GBM. We have designed, synthesized and tested in vitro and in vivo, a MAOB-specific prodrug version of OBG. The prodrug, PAM-OBG, does not inhibit MGMT but is converted to OBG by MAOB. This prodrug should therefore only generate high levels of OBG in tissues with high levels of MAOB; i.e. Glioma, and only these tissues will become hyper-sensitive to DNA-alkylating agents.