Oncotarget

Research Papers:

PAM-OBG: A monoamine oxidase B specific prodrug that inhibits MGMT and generates DNA interstrand crosslinks, potentiating temozolomide and chemoradiation therapy in intracranial glioblastoma

Martyn A. Sharpe _, Sudhir Raghavan and David S. Baskin

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Oncotarget. 2018; 9:23923-23943. https://doi.org/10.18632/oncotarget.25246

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Abstract

Martyn A. Sharpe1, Sudhir Raghavan1 and David S. Baskin1

1Department of Neurosurgery, Kenneth R. Peak Brain and Pituitary Tumor Center, Houston Methodist Hospital, TX 77030, Houston, USA

Correspondence to:

Martyn A. Sharpe, email: masharpe@houstonmethodist.org

David S. Baskin, email: dBaskin@houstonmethodist.org

Keywords: glioblastoma; MGMT; MAOB; drug; chemotherapy

Received: February 07, 2018     Accepted: April 08, 2018     Published: May 08, 2018

ABSTRACT

Via extensive analyses of genetic databases, we have characterized the DNA-repair 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.


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