Cadd-19. Pam-obg: a Maob-specific Prodrug Inhibitor of O6-methylguanine Dna Methyltransferase (mgmt) That Sensitizes Gmb to Bcnu/ccnu
Year: 2018
Type: article
Abstract: MGMT 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. PAM-OBG was synthesized by conventional chemistry. Enzyme kinetics, activity in vitro and in an in vivo intracranial primary GMB nude mouse model studies were performed in a manner similar to our previously reported work on MAOB prodrugs. PAM-OBG is a highly specific MAOB substrate, with a Km of only 200 microMolar. In tissue culture it is highly effective at inhibiting MGMT in cells with high MAOB activity, but not in cells where MAOB is inhibited. In an intracranial model of primary GBM we find that PAM-OBG is not toxic. It does however sensitize the brain tumors to the DNA-alkylating agents BCNU and CCNU. The efficacy of PAM-OBG with BCNU and CCNU, based on animal survival time, is six-fold. No increased toxicity of these chemotherapeutics is observed in off-target mouse tissues. We have developed a drug candidate prodrug to complement existing GBM therapy. We hope that PAM-OBG can be used to sensitize a patient’s GBM to DNA-alkylating agents, during and following, radiotherapy.
Source: Neuro-Oncology
Authors: Martyn Sharpe, David Baskin
Institution: Houston Methodist
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2900138688