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dc.contributor.authorBarvaux, Vincent A
dc.contributor.authorLorigan, Paul C
dc.contributor.authorRanson, Malcolm R
dc.contributor.authorGillum, Amanda M
dc.contributor.authorMcElhinney, R Stanley
dc.contributor.authorMcMurry, T Brian H
dc.contributor.authorMargison, Geoffrey P
dc.date.accessioned2009-08-21T09:59:22Z
dc.date.available2009-08-21T09:59:22Z
dc.date.issued2004-10
dc.identifier.citationSensitization 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.issn1535-7163
dc.identifier.pmid15486188
dc.identifier.urihttp://hdl.handle.net/10541/78127
dc.description.abstractTemozolomide 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.isoenen
dc.subjectOvarian Canceren
dc.subjectCell Line Tumouren
dc.subject.meshAntineoplastic Agents
dc.subject.meshAntineoplastic Agents, Alkylating
dc.subject.meshApoptosis
dc.subject.meshCell Line, Tumor
dc.subject.meshDNA Repair
dc.subject.meshDacarbazine
dc.subject.meshDose-Response Relationship, Drug
dc.subject.meshFemale
dc.subject.meshHumans
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase
dc.subject.meshOligonucleotides
dc.subject.meshOvarian Neoplasms
dc.subject.meshProto-Oncogene Proteins c-bcl-2
dc.subject.meshTetrazolium Salts
dc.subject.meshThiazoles
dc.subject.meshThionucleotides
dc.subject.meshTime Factors
dc.subject.meshUp-Regulation
dc.titleSensitization 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.typeArticleen
dc.contributor.departmentPaterson Institute for Cancer Research, Wilmslow Road, Manchester M204BX, UK.en
dc.identifier.journalMolecular Cancer Therapeuticsen
html.description.abstractTemozolomide 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.


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