|
|
O6-benzylguanine-mediated
enhancement of chemotherapy
Friedman HS, Keir S, Pegg AE, Houghton PJ, Colvin OM, Moschel RC,
Bigner DD, Dolan ME
Departments of Surgery, Pathology and Medicine, Duke
University Medical Center, Room 047, Baker House, Trent Drive, Durham, North
Carolina 27710, USA
We have previously demonstrated (A. E. Pegg, Cancer Res., 50: 6119-6129,
1990) that O6-benzylguanine (O6-BG) enhances nitrosourea, temozolomide, and
cyclophosphamide activity in malignant glioma xenografts growing in athymic nude
mice.
More recently, we have demonstrated (V. J. Patel et al., Clin. Cancer Res., 6:
4154-4157, 2000; P. Pourquier et al., Cancer Res., 61: 53-58, 2001) that the
combination of temozolomide plus irinotecan (CPT-11) displays a
schedule-dependent enhancement of antitumor activity secondary to trapping of
topoisomerase I by O6-methylguanine residues in DNA.
These studies suggested that there might be favorable therapeutic interactions
between O6-BG and combinations of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)
plus cyclophosphamide or temozolomide plus CPT-11, respectively.
Our present results indicate that the combination of cyclophosphamide plus BCNU
plus O6-BG produces growth delays modestly-to-markedly-superior to combinations
of cyclophosphamide with BCNU.
Although the combination of temozolomide and CPT-11 reveals a marked increase in
activity compared with either agent used alone, the addition of O6-BG to this
combination dramatically increased the growth delay of the O6-alkylguanine-DNA
alkyltransferase (AGT)-positive malignant glioma D-456 MG.
These results suggest that a Phase I trial of CPT-11 plus temozolomide plus
O6-BG in AGT-positive tumors may be an important intervention to maximize the
therapeutic benefits of the combination of CPT-11 and temozolomide.
PMID: 12481416 [PubMed - in process]
Source:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12481416&dopt=Abstract
|
