Sensitization of a human ovarian cancer cell line to temozolomide by simultaneous attenuation of the Bcl-2 antiapoptotic protein and DNA repair by O6-alkylguanine-DNA alkyltransferase.
Authors
Barvaux, Vincent ALorigan, Paul C
Ranson, Malcolm R
Gillum, Amanda M
McElhinney, R Stanley
McMurry, T Brian H
Margison, Geoffrey P
Affiliation
Paterson Institute for Cancer Research, Wilmslow Road, Manchester M204BX, UK.Issue Date
2004-10
Metadata
Show full item recordAbstract
Temozolomide is an alkylating agent that mediates its cytotoxic effects via O(6)-methylguanine (O(6)-meG) adducts in DNA. O(6)-alkylguanine-DNA-alkyltransferase (MGMT) can repair such adducts and therefore constitutes a major resistance mechanism to the drug. MGMT activity can be attenuated in vitro and in vivo by the pseudosubstrate O(6)-(4-bromothenyl)guanine (PaTrin-2, Patrin, Lomeguatrib), which in clinical trials is in combination with temozolomide. Resistance to cytotoxic agents can also be mediated by the Bcl-2 protein, which inhibits apoptosis and is frequently up-regulated in tumor cells. Attenuation of Bcl-2 expression can be affected by treatment of cells with the antisense oligonucleotide, oblimersen sodium (Genasense), currently in phase III clinical trials in combination with the methylating agent dacarbazine. Using a human ovarian cancer cell line (A2780) that expresses both Bcl-2 and MGMT, we show that cells treated with active dose levels of either oblimersen (but not control reverse sequence or mismatch oligonucleotides) or PaTrin-2 are substantially sensitized to temozolomide. Furthermore, the exposure of oblimersen-pretreated cells to PaTrin-2 leads to an even greater sensitization of these cells to temozolomide. Thus, growth of cells treated only with temozolomide (5 microg/mL) was 91% of control growth, whereas additional exposure to PaTrin-2 alone (10 micromol/L) or oblimersen alone (33 nmol/L) reduced this to 81% and 66%, respectively, and the combination of PaTrin-2 (10 micromol/L) and oblimersen (33 nmol/L) reduced growth to 25% of control. These results suggest that targeting both Bcl-2 with oblimersen and MGMT with PaTrin-2 would markedly enhance the antitumor activity of temozolomide and merits testing in clinical trials.Citation
Sensitization of a human ovarian cancer cell line to temozolomide by simultaneous attenuation of the Bcl-2 antiapoptotic protein and DNA repair by O6-alkylguanine-DNA alkyltransferase. 2004, 3 (10):1215-20 Mol. Cancer Ther.Journal
Molecular Cancer TherapeuticsPubMed ID
15486188Type
ArticleLanguage
enISSN
1535-7163Related articles
- O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts.
- Authors: Clemons M, Kelly J, Watson AJ, Howell A, McElhinney RS, McMurry TB, Margison GP
- Issue date: 2005 Nov 14
- Dual repair modulation reverses Temozolomide resistance in vitro.
- Authors: Barvaux VA, Ranson M, Brown R, McElhinney RS, McMurry TB, Margison GP
- Issue date: 2004 Feb
- The P140K mutant of human O(6)-methylguanine-DNA-methyltransferase (MGMT) confers resistance in vitro and in vivo to temozolomide in combination with the novel MGMT inactivator O(6)-(4-bromothenyl)guanine.
- Authors: Woolford LB, Southgate TD, Margison GP, Milsom MD, Fairbairn LJ
- Issue date: 2006 Jan
- O6-(4-bromothenyl)guanine (PaTrin-2), a novel inhibitor of O6-alkylguanine DNA alkyl-transferase, increases the inhibitory activity of temozolomide against human acute leukaemia cells in vitro.
- Authors: Turriziani M, Caporaso P, Bonmassar L, Buccisano F, Amadori S, Venditti A, Cantonetti M, D'Atri S, Bonmassar E
- Issue date: 2006 Apr
- Sensitization of pancreatic tumor xenografts to carmustine and temozolomide by inactivation of their O6-Methylguanine-DNA methyltransferase with O6-benzylguanine or O6-benzyl-2'-deoxyguanosine.
- Authors: Kokkinakis DM, Ahmed MM, Chendil D, Moschel RC, Pegg AE
- Issue date: 2003 Sep 1