IFN-{beta} sensitizes neuroblastoma to the antitumor activity of temozolomide by modulating O6-methylguanine DNA methyltransferase expression.
 

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12-06-08 08:55 AM
Anonymous
IFN-{beta} sensitizes neuroblastoma to the antitumor activity of temozolomide by modulating O6-methylguanine DNA methyltransferase expression.
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IFN-{beta} sensitizes neuroblastoma to the antitumor activity of temozolomide by modulating O6-methylguanine DNA methyltransferase expression.

Mol Cancer Ther. 2008 Dec 3;

Authors: Rosati SF, Williams RF, Nunnally LC, McGee MC, Sims TL, Tracey L, Zhou J, Fan M, Ng CY, Nathwani AC, Stewart CF, Pfeffer LM, Davidoff AM

Although temozolomide has shown clinical activity against neuroblastoma, this activity is likely limited by the DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT). We hypothesized that IFN-beta 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-beta 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-beta 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-beta 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-beta 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-beta); 352 +/- 110%, P = 0.0001 (combo)] and disseminated [bioluminescent signal: control (1.32e(10) +/- 6.5e(9)) versus IFN-beta (2.78e(8) +/- 3.09e(8)), P = 0.025, versus temozolomide (2.06e(9) +/- 1.55e(9)), P = 0.1, versus combination (2.13e(7) +/- 7.67e(6)), P = 0.009]. IFN-beta appears to sensitize neuroblastoma cells to the cytotoxic effects of temozolomide through attenuation of MGMT expression. Thus, IFN-beta and temozolomide may be a useful combination for treating children with this difficult disease. [Mol Cancer Ther 2008;7(12):3852-8].

PMID: 19056675 [PubMed - as supplied by publisher]