IFN-beta sensitizes neuroblastoma to the antitumor activity of temozolomide by modulating O6-methylguanine DNA methyltransferase expression.
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-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 (1.32e10 +/- 6.5e9) versus IFN-beta (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-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.
Rosati
Shannon F
SF
Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Williams
Regan F
RF
Nunnally
Lindsey C
LC
McGee
Mackenzie C
MC
Sims
Thomas L
TL
Tracey
Lorraine
L
Zhou
Junfang
J
Fan
Meiyun
M
Ng
Catherine Y
CY
Nathwani
Amit C
AC
Stewart
Clinton F
CF
Pfeffer
Lawrence M
LM
Davidoff
Andrew M
AM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism*; D007378:Interleukins / Q000502:physiology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D000077204:Temozolomide; D000099180:Interleukin-24
D000970:Antineoplastic Agents; D003606:Dacarbazine; D016899:Interferon-beta; D007378:Interleukins; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide; D000099180:Interleukin-24