IFN-β sensitizes neuroblastoma to the antitumor activity of temozolomide by modulating O6-methylguanine DNA methyltransferase expression
| العنوان: | IFN-β sensitizes neuroblastoma to the antitumor activity of temozolomide by modulating O6-methylguanine DNA methyltransferase expression |
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| المؤلفون: | Mackenzie McGee, Amit C. Nathwani, Thomas L. Sims, Clinton F. Stewart, Meiyun Fan, Junfang Zhou, Catherine Y.C. Ng, Lawrence M. Pfeffer, Lindsey C. Nunnally, Lorraine Tracey, Andrew M. Davidoff, Shannon F. Rosati, Regan F. Williams |
| المصدر: | Molecular Cancer Therapeutics. 7:3852-3858 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2008. |
| سنة النشر: | 2008 |
| مصطلحات موضوعية: | Male, Cancer Research, Combination therapy, DNA repair, Dacarbazine, Antineoplastic Agents, Mice, SCID, Biology, Article, Gene Expression Regulation, Enzymologic, Mice, Neuroblastoma, O(6)-Methylguanine-DNA Methyltransferase, Cell Line, Tumor, Glioma, Temozolomide, medicine, Animals, Humans, Neoplasm, neoplasms, Interleukins, O-6-methylguanine-DNA methyltransferase, Interferon-beta, medicine.disease, Gene Expression Regulation, Neoplastic, Oncology, Drug Resistance, Neoplasm, Immunology, Cancer research, Neoplasm Transplantation, medicine.drug |
| الوصف: | Although temozolomide has shown clinical activity against neuroblastoma, this activity is likely limited by the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT). We hypothesized that IFN-β could sensitize neuroblastoma cells to the cytotoxic effects of temozolomide through its ability to down-regulate MGMT expression. In vitro proliferation of three neuroblastoma cell lines treated with IFN-β and temozolomide alone or in combination was examined. Antitumor activity was assessed in both localized and disseminated neuroblastoma xenografts using single-agent and combination therapy, with continuous delivery of IFN-β being established by a liver-targeted adeno-associated virus-mediated approach. Two neuroblastoma cell lines (NB-1691 and SK-N-AS) were found to have high baseline levels of MGMT expression, whereas a third cell line (CHLA-255) had low levels. Temozolomide had little effect on in vitro proliferation of the neuroblastoma cell lines with high MGMT expression, but pretreatment with IFN-β significantly decreased MGMT expression and cell counts (NB-1691: 36 ± 3% of control, P = 0.0008; SK-N-AS: 54 ± 7% control, P = 0.003). In vivo, NB-1691 tumors in CB17-SCID mice treated with the combination of IFN-β and temozolomide had lower MGMT expression and a significantly reduced tumor burden, both localized [percent initial tumor volume: 2,516 ± 680% (control) versus 1,272 ± 330% (temozolomide), P = 0.01; 1,348 ± 220%, P = 0.03 (IFN-β); 352 ± 110%, P = 0.0001 (combo)] and disseminated [bioluminescent signal: control (1.32e10 ± 6.5e9) versus IFN-β (2.78e8 ± 3.09e8), P = 0.025, versus temozolomide (2.06e9 ± 1.55e9), P = 0.1, versus combination (2.13e7 ± 7.67e6), P = 0.009]. IFN-β appears to sensitize neuroblastoma cells to the cytotoxic effects of temozolomide through attenuation of MGMT expression. Thus, IFN-β and temozolomide may be a useful combination for treating children with this difficult disease. [Mol Cancer Ther 2008;7(12):3852–8] |
| تدمد: | 1538-8514 1535-7163 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7d3c47bddc1c5cce50eb8768bfd9198fTest https://doi.org/10.1158/1535-7163.mct-08-0806Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....7d3c47bddc1c5cce50eb8768bfd9198f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15388514 15357163 |
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