Abstract | PURPOSE: EXPERIMENTAL DESIGN: RESULTS:
Temozolomide enhances radiation response most effectively in glioblastomas without detectable MGMT expression. On concurrent radiation + temozolomide administration in MGMT-negative glioblastomas, there seems to be decreased double-strand DNA (dsDNA) repair capacity and enhanced dsDNA damage compared either with radiation alone or with sequentially administered temozolomide. Our data suggest that O(6)-benzylguanine can enhance the antitumor effects of concurrent radiation + temozolomide in MGMT-positive cells by enhancing apoptosis and the degree of dsDNA damage. O(6)-Benzylguanine was most effective when administered concurrently with radiation + temozolomide and had less of an effect when administered with temozolomide in the absence of radiation or when administered sequentially with radiation. Our in vivo data using U87 xenografts confirmed our in vitro findings. CONCLUSIONS: The present study shows that temozolomide enhances radiation response most effectively in MGMT-negative glioblastomas by increasing the degree of radiation-induced double-strand DNA damage. In MGMT-positive glioblastomas, depletion of MGMT by the addition of O(6)-benzylguanine significantly enhances the antitumor effect of concurrent radiation + temozolomide. These are among the first data showing mechanisms of synergy between radiation and temozolomide and the effect of MGMT.
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Authors | Arnab Chakravarti, Michael G Erkkinen, Ulf Nestler, Roger Stupp, Minesh Mehta, Ken Aldape, Mark R Gilbert, Peter McL Black, Jay S Loeffler |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 12
Issue 15
Pg. 4738-46
(Aug 01 2006)
ISSN: 1078-0432 [Print] United States |
PMID | 16899625
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- O(6)-benzylguanine
- Guanine
- Dacarbazine
- O(6)-Methylguanine-DNA Methyltransferase
- Temozolomide
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Topics |
- Animals
- Apoptosis
(drug effects, radiation effects)
- Cell Line, Tumor
- Combined Modality Therapy
- DNA Damage
- Dacarbazine
(administration & dosage, analogs & derivatives, pharmacology)
- Disease Models, Animal
- Glioblastoma
(drug therapy, radiotherapy)
- Guanine
(administration & dosage, analogs & derivatives, pharmacology)
- Humans
- Methylation
- Mice
- Mice, Nude
- O(6)-Methylguanine-DNA Methyltransferase
(drug effects, metabolism, radiation effects)
- Structure-Activity Relationship
- Temozolomide
- Transplantation, Heterologous
- Xenograft Model Antitumor Assays
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