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.

2.50
Hdl Handle:
http://hdl.handle.net/10541/78127
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.
Authors:
Barvaux, Vincent A; Lorigan, Paul C ( 0000-0002-8875-2164 ) ; Ranson, Malcolm R; Gillum, Amanda M; McElhinney, R Stanley; McMurry, T Brian H; Margison, Geoffrey P
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.
Affiliation:
Paterson Institute for Cancer Research, Wilmslow Road, Manchester M204BX, UK.
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 Therapeutics
Issue Date:
Oct-2004
URI:
http://hdl.handle.net/10541/78127
PubMed ID:
15486188
Type:
Article
Language:
en
ISSN:
1535-7163
Appears in Collections:
All Christie Publications ; All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
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.en
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

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