PMID- 33323683
OWN - NLM
STAT- MEDLINE
DCOM- 20211026
LR  - 20230901
IS  - 1473-5741 (Electronic)
IS  - 0959-4973 (Print)
IS  - 0959-4973 (Linking)
VI  - 32
IP  - 3
DP  - 2021 Mar 1
TI  - The O6-methyguanine-DNA methyltransferase inhibitor O6-benzylguanine enhanced 
      activity of temozolomide + irinotecan against models of high-risk neuroblastoma.
PG  - 233-247
LID - 10.1097/CAD.0000000000001020 [doi]
AB  - DNA-damaging chemotherapy is a major component of therapy for high-risk 
      neuroblastoma, and patients often relapse with treatment-refractory disease. We 
      hypothesized that DNA repair genes with increased expression in alkylating agent 
      resistant models would provide therapeutic targets for enhancing chemotherapy. 
      In-vitro cytotoxicity of alkylating agents for 12 patient-derived neuroblastoma 
      cell lines was assayed using DIMSCAN, and mRNA expression of 57 DNA repair, three 
      transporter, and two glutathione synthesis genes was assessed by TaqMan 
      low-density array (TLDA) with further validation by qRT-PCR in 26 cell lines. 
      O6-methylguanine-DNA methyltransferase (MGMT) mRNA was upregulated in cell lines 
      with greater melphalan and temozolomide (TMZ) resistance. MGMT expression also 
      correlated significantly with resistance to TMZ+irinotecan (IRN) (in-vitro as the 
      SN38 active metabolite). Forced overexpression of MGMT (lentiviral transduction) 
      in MGMT non-expressing cell lines significantly increased TMZ+SN38 resistance. 
      The MGMT inhibitor O6-benzylguanine (O6BG) enhanced TMZ+SN38 in-vitro 
      cytotoxicity, H2AX phosphorylation, caspase-3 cleavage, and apoptosis by terminal 
      deoxynucleotidyl transferase dUTP nick end labeling. TMZ+IRN+O6BG delayed tumor 
      growth and increased survival relative to TMZ+IRN in two of seven patient-derived 
      xenografts established at time of death from progressive neuroblastoma. We 
      demonstrated that high MGMT expression was associated with resistance to 
      alkylating agents and TMZ+IRN in preclinical neuroblastoma models. The MGMT 
      inhibitor O6BG enhanced the anticancer effect of TMZ+IRN in vitro and in vivo. 
      These results support further preclinical studies exploring MGMT as a therapeutic 
      target and biomarker of TMZ+IRN resistance in high-risk neuroblastoma.
CI  - Copyright (c) 2020 Wolters Kluwer Health, Inc. All rights reserved.
FAU - Hindle, Ashly
AU  - Hindle A
AD  - Cancer Center, School of Medicine, Texas Tech University Health Sciences Center.
AD  - Department of Cell Biology & Biochemistry, Texas Tech University Health Sciences 
      Center.
AD  - Departments of Internal Medicine.
FAU - Koneru, Balakrishna
AU  - Koneru B
AD  - Cancer Center, School of Medicine, Texas Tech University Health Sciences Center.
AD  - Department of Cell Biology & Biochemistry, Texas Tech University Health Sciences 
      Center.
AD  - Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, 
      Lubbock, Texas.
FAU - Makena, Monish Ram
AU  - Makena MR
AD  - Cancer Center, School of Medicine, Texas Tech University Health Sciences Center.
AD  - Department of Cell Biology & Biochemistry, Texas Tech University Health Sciences 
      Center.
AD  - Department of Physiology, Johns Hopkins School of Medicine, Baltimore, Maryland, 
      USA.
FAU - Lopez-Barcons, Lluis
AU  - Lopez-Barcons L
AD  - Cancer Center, School of Medicine, Texas Tech University Health Sciences Center.
AD  - Department of Cell Biology & Biochemistry, Texas Tech University Health Sciences 
      Center.
FAU - Chen, Wan Hsi
AU  - Chen WH
AD  - Cancer Center, School of Medicine, Texas Tech University Health Sciences Center.
AD  - Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, 
      Lubbock, Texas.
FAU - Nguyen, Thinh H
AU  - Nguyen TH
AD  - Cancer Center, School of Medicine, Texas Tech University Health Sciences Center.
FAU - Reynolds, C Patrick
AU  - Reynolds CP
AD  - Cancer Center, School of Medicine, Texas Tech University Health Sciences Center.
AD  - Department of Cell Biology & Biochemistry, Texas Tech University Health Sciences 
      Center.
AD  - Departments of Internal Medicine.
AD  - Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, 
      Lubbock, Texas.
LA  - eng
GR  - R01 CA221957/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Anticancer Drugs
JT  - Anti-cancer drugs
JID - 9100823
RN  - 0 (Antineoplastic Agents)
RN  - 0 (RNA, Messenger)
RN  - 01KC87F8FE (O(6)-benzylguanine)
RN  - 5Z93L87A1R (Guanine)
RN  - 7673326042 (Irinotecan)
RN  - EC 2.1.1.63 (O(6)-Methylguanine-DNA Methyltransferase)
RN  - YF1K15M17Y (Temozolomide)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/drug effects
MH  - Cell Line, Tumor
MH  - Cell Survival
MH  - DNA Repair/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Drug Resistance, Neoplasm/physiology
MH  - Guanine/*analogs & derivatives/pharmacology
MH  - Humans
MH  - Irinotecan/*pharmacology
MH  - Mice
MH  - Neuroblastoma/drug therapy
MH  - O(6)-Methylguanine-DNA Methyltransferase/*antagonists & inhibitors
MH  - RNA, Messenger
MH  - Real-Time Polymerase Chain Reaction
MH  - Temozolomide/*pharmacology
MH  - Up-Regulation
PMC - PMC9255907
MID - NIHMS1818486
COIS- Conflicts of interest statement: The authors declare no potential conflicts of 
      interest.
EDAT- 2020/12/17 06:00
MHDA- 2021/10/27 06:00
PMCR- 2022/07/05
CRDT- 2020/12/16 05:29
PHST- 2020/12/17 06:00 [pubmed]
PHST- 2021/10/27 06:00 [medline]
PHST- 2020/12/16 05:29 [entrez]
PHST- 2022/07/05 00:00 [pmc-release]
AID - 00001813-202103000-00002 [pii]
AID - 10.1097/CAD.0000000000001020 [doi]
PST - ppublish
SO  - Anticancer Drugs. 2021 Mar 1;32(3):233-247. doi: 10.1097/CAD.0000000000001020.