Temozolomide-mediated radiation enhancement in glioblastoma: a report on underlying mechanisms.
Chakravarti A, Erkkinen MG, Nestler U, Stupp R, Mehta M, Aldape K, Gilbert MR, Black PM, Loeffler JS.
Authors' Affiliations: Department of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School.
PURPOSE:
In this study, we investigated the mechanisms by which temozolomide enhances radiation response in glioblastoma cells.
EXPERIMENTAL DESIGN:
Using a panel of four primary human glioblastoma cell lines with heterogeneous O(6)-methylguanine-DNA methyltransferase (MGMT) protein expression, normal human astrocytes, and U87 xenografts,
we investigated
(a) the relationship of MGMT status with efficacy of temozolomide-based chemoradiation using a panel of in vitro and in vivo assays;
(b) underlying mechanisms by which temozolomide enhances radiation effect in glioblastoma cells; and
(c) strategies to overcome resistance to radiation + temozolomide.
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.
PMID: 16899625 [PubMed - in process]
ncbi.nlm.nih.gov
Note:
re:
O(6)-Benzylguanine
30)
Gliadel Wafer and O6-Benzylguanine in Treating Patients With Recurrent Glioblastoma Multiforme
Sponsors and Collaborators: Duke University
National Cancer Institute (NCI)
Purpose
RATIONALE: Drugs used in chemotherapy, such as Gliadel wafer and O6-benzylguanine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells.
PURPOSE: This phase II trial is studying how well giving Gliadel wafer together with O6-benzylguanine works in treating patients with recurrent glioblastoma multiforme.
clinicaltrials.gov
ncbi.nlm.nih.gov
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(53)
Treatment of Newly Diagnosed Brain Tumors With Chemotherapy and Radiation Using Cells Modified for Chemoprotection and an Experimental Drug to Decrease the Tumor Cell Resistance to Chemotherapy
Sponsored by: Children's Hospital Medical Center - Cincinnati
Purpose
Cure rates for patients with high grade glioma remain disappointing, in part because tumor cells are often resistant to chemotherapy, and because using higher doses of chemotherapy causes damage to normal blood cells. This trial is designed to try to overcome both of these barriers. The idea is to make tumor cells more sensitive to a chemotherapy agent, Temozolomide, by using 06Benzylguanine (06BG). In addition, patients will have a portion of their blood cells modified by the insertion of a chemotherapy resistance gene which may help protect blood cells from damage by the combination of the Temozolomide and 06BG.
clinicaltrials.gov
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Treatment of Newly Diagnosed Brain Tumors With Chemotherapy and Radiation Using Cells Modified for Chemoprotection and an Experimental Drug to Decrease the Tumor Cell Resistance to Chemotherapy
This study is currently recruiting patients.
Verified by Children's Hospital Medical Center - Cincinnati December 2005
Sponsored by: Children's Hospital Medical Center - Cincinnati
Information provided by: Children's Hospital Medical Center - Cincinnati
ClinicalTrials.gov Identifier: NCT00272870
Purpose
Cure rates for patients with high grade glioma remain disappointing, in part because tumor cells are often resistant to chemotherapy, and because using higher doses of chemotherapy causes damage to normal blood cells. This trial is designed to try to overcome both of these barriers. The idea is to make tumor cells more sensitive to a chemotherapy agent, Temozolomide, by using 06Benzylguanine (06BG). In addition, patients will have a portion of their blood cells modified by the insertion of a chemotherapy resistance gene which may help protect blood cells from damage by the combination of the Temozolomide and 06BG.
clinicaltrials.gov |
