IFN-β sensitizes neuroblastoma to the antitumor activity of temozolomide by modulating O6-methylguanine DNA methyltransferase expression

Shannon F. Rosati, Regan Williams, Lindsey C. Nunnally, Mackenzie C. McGee, Thomas L. Sims, Lorraine Tracey, Junfang Zhou, Meiyun Fan, Catherine Y. Ng, Amit C. Nathwani, Clinton F. Stewart, Lawrence Pfeffer, Andrew M. Davidoff

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)3852-3858
Number of pages7
JournalMolecular Cancer Therapeutics
Volume7
Issue number12
DOIs
StatePublished - Dec 1 2008

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temozolomide
Methyltransferases
Neuroblastoma
DNA
Cell Line
Tumor Burden
DNA Repair Enzymes
O-(6)-methylguanine
Dependovirus
SCID Mice

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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IFN-β sensitizes neuroblastoma to the antitumor activity of temozolomide by modulating O6-methylguanine DNA methyltransferase expression. / Rosati, Shannon F.; Williams, Regan; Nunnally, Lindsey C.; McGee, Mackenzie C.; Sims, Thomas L.; Tracey, Lorraine; Zhou, Junfang; Fan, Meiyun; Ng, Catherine Y.; Nathwani, Amit C.; Stewart, Clinton F.; Pfeffer, Lawrence; Davidoff, Andrew M.

In: Molecular Cancer Therapeutics, Vol. 7, No. 12, 01.12.2008, p. 3852-3858.

Research output: Contribution to journalArticle

Rosati, Shannon F. ; Williams, Regan ; Nunnally, Lindsey C. ; McGee, Mackenzie C. ; Sims, Thomas L. ; Tracey, Lorraine ; Zhou, Junfang ; Fan, Meiyun ; Ng, Catherine Y. ; Nathwani, Amit C. ; Stewart, Clinton F. ; Pfeffer, Lawrence ; Davidoff, Andrew M. / IFN-β sensitizes neuroblastoma to the antitumor activity of temozolomide by modulating O6-methylguanine DNA methyltransferase expression. In: Molecular Cancer Therapeutics. 2008 ; Vol. 7, No. 12. pp. 3852-3858.
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abstract = "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.",
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T1 - IFN-β sensitizes neuroblastoma to the antitumor activity of temozolomide by modulating O6-methylguanine DNA methyltransferase expression

AU - Rosati, Shannon F.

AU - Williams, Regan

AU - Nunnally, Lindsey C.

AU - McGee, Mackenzie C.

AU - Sims, Thomas L.

AU - Tracey, Lorraine

AU - Zhou, Junfang

AU - Fan, Meiyun

AU - Ng, Catherine Y.

AU - Nathwani, Amit C.

AU - Stewart, Clinton F.

AU - Pfeffer, Lawrence

AU - Davidoff, Andrew M.

PY - 2008/12/1

Y1 - 2008/12/1

N2 - 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.

AB - 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.

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