PMID- 29844863
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20191120
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 9
IP  - 35
DP  - 2018 May 8
TI  - PAM-OBG: A monoamine oxidase B specific prodrug that inhibits MGMT and generates 
      DNA interstrand crosslinks, potentiating temozolomide and chemoradiation therapy 
      in intracranial glioblastoma.
PG  - 23923-23943
LID - 10.18632/oncotarget.25246 [doi]
AB  - 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 O(6)-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 O(6)-benzylguanine (O(6)BG) and the DNA crosslinking 
      agent acrolein. In cultured glioma cells, we show that PAM-OBG is converted to 
      O(6)BG, 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.
FAU - Sharpe, Martyn A
AU  - Sharpe MA
AD  - Department of Neurosurgery, Kenneth R. Peak Brain and Pituitary Tumor Center, 
      Houston Methodist Hospital, TX 77030, Houston, USA.
FAU - Raghavan, Sudhir
AU  - Raghavan S
AD  - Department of Neurosurgery, Kenneth R. Peak Brain and Pituitary Tumor Center, 
      Houston Methodist Hospital, TX 77030, Houston, USA.
FAU - Baskin, David S
AU  - Baskin DS
AD  - Department of Neurosurgery, Kenneth R. Peak Brain and Pituitary Tumor Center, 
      Houston Methodist Hospital, TX 77030, Houston, USA.
LA  - eng
PT  - Journal Article
DEP - 20180508
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
PMC - PMC5963626
OTO - NOTNLM
OT  - MAOB
OT  - MGMT
OT  - chemotherapy
OT  - drug
OT  - glioblastoma
COIS- CONFLICTS OF INTEREST The authors declare no conflicts of interest.
EDAT- 2018/05/31 06:00
MHDA- 2018/05/31 06:01
PMCR- 2018/05/08
CRDT- 2018/05/31 06:00
PHST- 2018/02/07 00:00 [received]
PHST- 2018/04/08 00:00 [accepted]
PHST- 2018/05/31 06:00 [entrez]
PHST- 2018/05/31 06:00 [pubmed]
PHST- 2018/05/31 06:01 [medline]
PHST- 2018/05/08 00:00 [pmc-release]
AID - 25246 [pii]
AID - 10.18632/oncotarget.25246 [doi]
PST - epublish
SO  - Oncotarget. 2018 May 8;9(35):23923-23943. doi: 10.18632/oncotarget.25246. 
      eCollection 2018 May 8.