@article{61227b47335a464db307e01233fb4a38,
title = "PAM-OBG: A monoamine oxidase B specific prodrug that inhibits MGMT and generates DNA interstrand crosslinks, potentiating temozolomide and chemoradiation therapy in intracranial glioblastoma",
abstract = "Via extensive analyses of genetic databases, we have characterized the DNArepair capacity of glioblastoma with respect to patient survival. In addition to elevation of O6-methylguanine DNA methyltransferase (MGMT), down-regulation of three DNA repair pathways; canonical mismatch repair (MMR), Non-Homologous End-Joining (NHEJ), and Homologous Recombination (HR) are correlated with poor patient outcome. We have designed and tested both in vitro and in vivo, a monoamine oxidase B (MAOB) specific prodrug, PAM-OBG, that is converted by glioma MAOB into the MGMT inhibitor O6-benzylguanine (O6BG) and the DNA crosslinking agent acrolein. In cultured glioma cells, we show that PAM-OBG is converted to O6BG, inhibiting MGMT and sensitizing cells to DNA alkylating agents such as BCNU, CCNU, and Temozolomide (TMZ). In addition, we demonstrate that the acrolein generated is highly toxic in glioma treated with an inhibitor of Nucleotide Excision Repair (NER). In mouse intracranial models of primary human glioma, we show that PAM-OBG increases survival of mice treated with either BCNU or CCNU by a factor of six and that in a chemoradiation model utilizing six rounds of TMZ/2Gy radiation, pre-treatment with PAM-OBG more than doubled survival time.",
keywords = "Chemotherapy, Drug, Glioblastoma, MAOB, MGMT",
author = "Sharpe, {Martyn A.} and Sudhir Raghavan and Baskin, {David S.}",
note = "Funding Information: work was supported by the Donna and Kenneth R. Peak Foundation, The Kenneth R. Peak Brain and Pituitary Center at Houston Methodist Hospital, The Taub Foundation, The Blanche Green Estate Fund of the Pauline Sterne Wolff Memorial Foundation, The John S. Dunn Foundation, The American Brain Tumor Association, The Marilee A. and Gary M. Schwarz Foundation, The Houston Methodist Hospital Foundation, and the Verelan Foundation. We are grateful to the many patients and families whose lives have been changed by the devastating effects of brain tumors who have helped us with our research. Funding Information: Work at the Houston Methodist Hospital: This work was supported by the Donna and Kenneth R. Peak Foundation, The Kenneth R. Peak Brain and Pituitary Center at Houston Methodist Hospital, The Taub Foundation, The Blanche Green Estate Fund of the Pauline Sterne Wolff Memorial Foundation, The John S. Dunn Foundation, The American Brain Tumor Association, The Marilee A. and Gary M. Schwarz Foundation, The Houston Methodist Hospital Foundation, and the Verelan Foundation. We are grateful to the many patients and families whose lives have been changed by the devastating effects of brain tumors who have helped us with our research. Publisher Copyright: {\textcopyright} Sharpe et al.",
year = "2018",
month = may,
day = "1",
doi = "10.18632/oncotarget.25246",
language = "English (US)",
volume = "9",
pages = "23923--23943",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "35",
}