The O6-methyguanine-DNA methyltransferase inhibitor O6-benzylguanine enhanced activity of temozolomide + irinotecan against models of high-risk neuroblastoma.
Anticancer Drugs
; 32(3): 233-247, 2021 03 01.
Article
en En
| MEDLINE
| ID: mdl-33323683
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
O(6)-Metilguanina-ADN Metiltransferasa
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Irinotecán
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Temozolomida
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Guanina
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Antineoplásicos
Tipo de estudio:
Etiology_studies
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Risk_factors_studies
Límite:
Animals
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Humans
Idioma:
En
Revista:
Anticancer Drugs
Asunto de la revista:
ANTINEOPLASICOS
Año:
2021
Tipo del documento:
Article