New (alternative) temozolomide regimens for the treatment of glioma.
One barrier to successful treatment of malignant glioma is resistance to alkylating agents such as temozolomide. The cytotoxic activity of temozolomide and other alkylating agents is believed to manifest largely by the formation of O(6)-methylguanine DNA adducts. Consequently, the primary mechanism of resistance to temozolomide is a function of the activity of the DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT). Fortuitously, MGMT is inactivated after each reaction (i.e., suicide enzyme). Therefore, if the rate of DNA alkylation were to outpace the rate of MGMT protein synthesis, the enzyme could, in theory, be depleted. Several studies have shown that prolonged exposure to temozolomide can deplete MGMT activity in blood cells, a process that could potentially increase the antitumor activity of the drug. To date, however, there are limited data demonstrating the depletion of MGMT activity in tumor tissue exposed to temozolomide. A variety of dosing schedules that increase the duration of exposure and the cumulative dose of temozolomide are currently being investigated for the treatment of glioma, with the goal of improving antitumor activity and overcoming resistance. These alternative dosing regimens have been shown to deplete MGMT activity in peripheral blood mononuclear cells, but the regimen that provides the best balance between enhanced antitumor activity and acceptable hematologic toxicity has yet to be determined.
Wick
Wolfgang
W
Department of Neurooncology, University Clinic of Heidelberg, Heidelberg, Germany. wolfgang.wick@med.uni-heidelberg.de
Platten
Michael
M
Weller
Michael
M
D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics*; D000077204:Temozolomide
D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide
Neuro Oncol. 2002 Oct;4(4):261-7
12356356
Oncogene. 2007 Jan 11;26(2):186-97
16819506
N Engl J Med. 2005 Mar 10;352(10):997-1003
15758010
Ann Oncol. 2005 Jun;16(6):942-9
15870090
Neurology. 2004 Jun 8;62(11):2113-5
15184628
J Clin Oncol. 1998 Dec;16(12):3851-7
9850030
Br J Cancer. 2006 Nov 6;95(9):1155-60
17024124
J Clin Oncol. 2008 Sep 1;26(25):4189-99
18757334
N Engl J Med. 2005 Mar 10;352(10):987-96
15758009
J Natl Cancer Inst. 1993 May 5;85(9):704-10
8478956
Curr Med Chem. 2002 Jul;9(13):1285-301
12052167
Neuro Oncol. 2004 Jan;6(1):28-32
14769137
Oncologist. 2006 Feb;11(2):165-80
16476837
Cancer Res. 1999 Feb 15;59(4):793-7
10029064
J Clin Oncol. 2005 Apr 1;23(10):2372-7
15800329
Cancer Res. 1998 Oct 1;58(19):4363-7
9766665
J Neurooncol. 2004 Jul;68(3):275-83
15332332
Mutat Res. 2000 Apr;462(2-3):71-82
10767619
Cancer. 2008 Mar 1;112(5):1139-46
18246536
Br J Cancer. 1992 Feb;65(2):287-91
1739631
J Clin Oncol. 2010 Apr 20;28(12):2051-7
20308655
Prog Nucleic Acid Res Mol Biol. 1995;51:167-223
7659775
N Engl J Med. 2000 Nov 9;343(19):1350-4
11070098
Br J Cancer. 2003 Apr 7;88(7):1004-11
12671695
J Neurooncol. 1994;21(2):135-40
7861189
Clin Cancer Res. 1999 Oct;5(10):2908-17
10537360
Cancer Treat Rev. 1997 Jan;23(1):35-61
9189180
Cancer Res. 2005 Jul 15;65(14):6394-400
16024643
Neurosurgery. 2004 Feb;54(2):349-57; discussion 357
14744281
Int J Oncol. 2003 Mar;22(3):601-8
12579314
Neuro Oncol. 2002 Jan;4(1):39-43
11772431
Proc Natl Acad Sci U S A. 1990 Jan;87(2):686-90
2405387
J Clin Oncol. 2005 Jun 20;23(18):4235-6; author reply 4236
15961774
Mol Cell Biol. 1997 Sep;17(9):5612-9
9271436
J Clin Oncol. 2007 Aug 1;25(22):3357-61
17664483
Clin Cancer Res. 2001 Aug;7(8):2309-17
11489806
J Clin Oncol. 2007 Apr 20;25(12):1470-5
17442989
Strahlenther Onkol. 2005 Jun;181(6):372-7
15925979
Cancer Res. 1987 Nov 15;47(22):5846-52
3664486
J Clin Oncol. 2002 Mar 1;20(5):1375-82
11870182
J Clin Oncol. 1999 Sep;17(9):2762-71
10561351
Br J Cancer. 1994 Mar;69(3):452-6
8123472
J Clin Oncol. 2004 Feb 15;22(4):610-6
14726505
Cancer Res. 1999 May 15;59(10):2402-10
10344750
Cancer Invest. 2008 Apr-May;26(3):269-77
18317968
Int J Cancer. 2000 Nov 1;88(3):469-73
11054678
J Neurooncol. 2007 Aug;84(1):71-7
17361334
Br J Cancer. 2000 Sep;83(5):588-93
10944597