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.
dc.contributor.author | Barvaux, Vincent A | |
dc.contributor.author | Lorigan, Paul C | |
dc.contributor.author | Ranson, Malcolm R | |
dc.contributor.author | Gillum, Amanda M | |
dc.contributor.author | McElhinney, R Stanley | |
dc.contributor.author | McMurry, T Brian H | |
dc.contributor.author | Margison, Geoffrey P | |
dc.date.accessioned | 2009-08-21T09:59:22Z | |
dc.date.available | 2009-08-21T09:59:22Z | |
dc.date.issued | 2004-10 | |
dc.identifier.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. | en |
dc.identifier.issn | 1535-7163 | |
dc.identifier.pmid | 15486188 | |
dc.identifier.uri | http://hdl.handle.net/10541/78127 | |
dc.description.abstract | 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. | |
dc.language.iso | en | en |
dc.subject | Ovarian Cancer | en |
dc.subject | Cell Line Tumour | en |
dc.subject.mesh | Antineoplastic Agents | |
dc.subject.mesh | Antineoplastic Agents, Alkylating | |
dc.subject.mesh | Apoptosis | |
dc.subject.mesh | Cell Line, Tumor | |
dc.subject.mesh | DNA Repair | |
dc.subject.mesh | Dacarbazine | |
dc.subject.mesh | Dose-Response Relationship, Drug | |
dc.subject.mesh | Female | |
dc.subject.mesh | Humans | |
dc.subject.mesh | O(6)-Methylguanine-DNA Methyltransferase | |
dc.subject.mesh | Oligonucleotides | |
dc.subject.mesh | Ovarian Neoplasms | |
dc.subject.mesh | Proto-Oncogene Proteins c-bcl-2 | |
dc.subject.mesh | Tetrazolium Salts | |
dc.subject.mesh | Thiazoles | |
dc.subject.mesh | Thionucleotides | |
dc.subject.mesh | Time Factors | |
dc.subject.mesh | Up-Regulation | |
dc.title | 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. | en |
dc.type | Article | en |
dc.contributor.department | Paterson Institute for Cancer Research, Wilmslow Road, Manchester M204BX, UK. | en |
dc.identifier.journal | Molecular Cancer Therapeutics | en |
html.description.abstract | 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. |