A combination of IFN-beta and temozolomide in human glioma xenograft models: implication of p53-mediated MGMT downregulation.
OBJECTIVE
Methylation of the O(6)-methyguanine-DNA methyltransferase (MGMT) gene promoter in gliomas has been reported to be a useful predictor of the responsiveness to temozolomide (TMZ). In our previous experiments, we observed that IFN-beta sensitized TMZ-resistant glioma cells with the unmethylated MGMT promoter and that the mechanism of action was possibly due to attenuation of MGMT expression via induction of TP53. In this study, (1) we explored the synergistic effect of IFN-beta and TMZ in the animal model, and (2) clarified the role of IFN-beta induced TP53 in the human MGMT promoter.


METHODS
(1) Nude mice with either subcutaneous T98 (TMZ-resistant) or U251SP (TMZ-sensitive) tumor were treated with IFN-beta/TMZ for 5 consecutive days. (2) The MGMT promoter activity was assayed by a luciferase reporter system in Saos2 (p53-null) cells transduced with a p53-adenoviral vector, and T98 glioma cells treated with IFN-beta.


RESULTS
(1) A combination of IFN-beta/TMZ had significant synergistic antitumor activity on the growth of both T98 and U251SP tumors. (2) MGMT promoter activity was suppressed by either adenovirally transduced p53 or IFN-beta.


CONCLUSIONS
It would be appealing to consider a prospective clinical trial in which genetic markers are used for personalized drug selection, eliciting other forms of treatment or inhibition of MGMT for those with MGMT expression. In this context, IFN-beta inactivates MGMT via p53 gene induction and enhances the therapeutic efficacy to TMZ.
Natsume
Atsushi
A
Department of Neurosurgery, Nagoya University School of Medicine, 65 Tsurumai, Showa-ku, Nagoya, 466-8550, Japan.
Wakabayashi
Toshihiko
T
Ishii
Dai
D
Maruta
Hideharu
H
Fujii
Masazumi
M
Shimato
Shinji
S
Ito
Motokazu
M
Yoshida
Jun
J
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D015536:Down-Regulation / Q000187:drug effects; D005134:Eye Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D017930:Genes, Reporter / Q000235:genetics; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007370:Interferon Type I / Q000008:administration & dosage; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors*; D010957:Plasmids / Q000235:genetics; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077204:Temozolomide; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D007370:Interferon Type I; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D003606:Dacarbazine; D008156:Luciferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide