O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts.

2.50
Hdl Handle:
http://hdl.handle.net/10541/76854
Title:
O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts.
Authors:
Clemons, Mark; Kelly, J; Watson, Amanda J; Howell, Anthony ( 0000-0002-3879-5991 ) ; McElhinney, R S; McMurry, T B H; Margison, Geoffrey P
Abstract:
Tumour resistance to chemotherapy involving methylating agents such as DTIC (dacarbazine) and temozolomide is linked to expression of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (MGMT). There is considerable interest in improving the efficacy of such O(6)-alkylating chemotherapy by the prior inactivation of MGMT. We have examined the effect of the modified guanine base, O(6)-(4-bromothenyl)guanine (PaTrin-2, Patrin, Lomeguatrib) on MGMT activity and cell or xenograft tumour growth inhibition by temozolomide in the human breast carcinosarcoma cell line, MCF-7. PaTrin-2 effectively inactivated MGMT in MCF-7 cells (IC(50) approximately 6 nM) and in xenografts there was complete inactivation of MGMT within 2 h of dosing (20 mg kg(-1) i.p.) and only slight recovery by 24 h. MGMT inactivation in a range of murine host tissues varied between complete and approximately 60%, with extensive recovery by 24 h. PaTrin-2 (10 microM) substantially increased the growth inhibitory effects of temozolomide in MCF-7 cells (D(60)=10 microM with PaTrin-2 vs 400 microM without). In MCF-7 xenografts, neither temozolomide (100 mg kg(-1) day(-1) for 5 days) nor PaTrin-2 (20 mg kg(-1) day(-1) for 5 days) had any significant effect on tumour growth. In contrast, the PaTrin-2-temozolomide combination produced a substantial tumour growth delay: median tumour quintupling time was increase by 22 days (P<0.005) without any significant increase in toxicity as assessed from animal weight. A PaTrin-2-temozolomide combination may therefore be beneficial in the treatment of human breast cancers.
Affiliation:
Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, Manchester M20 9BX, UK.
Citation:
O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts. 2005, 93 (10):1152-6 Br. J. Cancer
Journal:
British Journal of Cancer
Issue Date:
14-Nov-2005
URI:
http://hdl.handle.net/10541/76854
DOI:
10.1038/sj.bjc.6602833
PubMed ID:
16278661
Type:
Article
Language:
en
ISSN:
0007-0920
Appears in Collections:
All Christie Publications

Full metadata record

DC FieldValue Language
dc.contributor.authorClemons, Mark-
dc.contributor.authorKelly, J-
dc.contributor.authorWatson, Amanda J-
dc.contributor.authorHowell, Anthony-
dc.contributor.authorMcElhinney, R S-
dc.contributor.authorMcMurry, T B H-
dc.contributor.authorMargison, Geoffrey P-
dc.date.accessioned2009-08-10T17:25:11Z-
dc.date.available2009-08-10T17:25:11Z-
dc.date.issued2005-11-14-
dc.identifier.citationO6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts. 2005, 93 (10):1152-6 Br. J. Canceren
dc.identifier.issn0007-0920-
dc.identifier.pmid16278661-
dc.identifier.doi10.1038/sj.bjc.6602833-
dc.identifier.urihttp://hdl.handle.net/10541/76854-
dc.description.abstractTumour resistance to chemotherapy involving methylating agents such as DTIC (dacarbazine) and temozolomide is linked to expression of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (MGMT). There is considerable interest in improving the efficacy of such O(6)-alkylating chemotherapy by the prior inactivation of MGMT. We have examined the effect of the modified guanine base, O(6)-(4-bromothenyl)guanine (PaTrin-2, Patrin, Lomeguatrib) on MGMT activity and cell or xenograft tumour growth inhibition by temozolomide in the human breast carcinosarcoma cell line, MCF-7. PaTrin-2 effectively inactivated MGMT in MCF-7 cells (IC(50) approximately 6 nM) and in xenografts there was complete inactivation of MGMT within 2 h of dosing (20 mg kg(-1) i.p.) and only slight recovery by 24 h. MGMT inactivation in a range of murine host tissues varied between complete and approximately 60%, with extensive recovery by 24 h. PaTrin-2 (10 microM) substantially increased the growth inhibitory effects of temozolomide in MCF-7 cells (D(60)=10 microM with PaTrin-2 vs 400 microM without). In MCF-7 xenografts, neither temozolomide (100 mg kg(-1) day(-1) for 5 days) nor PaTrin-2 (20 mg kg(-1) day(-1) for 5 days) had any significant effect on tumour growth. In contrast, the PaTrin-2-temozolomide combination produced a substantial tumour growth delay: median tumour quintupling time was increase by 22 days (P<0.005) without any significant increase in toxicity as assessed from animal weight. A PaTrin-2-temozolomide combination may therefore be beneficial in the treatment of human breast cancers.en
dc.language.isoenen
dc.subjectBreast Canceren
dc.subjectCell Line Tumouren
dc.subject.meshAnimals-
dc.subject.meshBody Weight-
dc.subject.meshBreast Neoplasms-
dc.subject.meshCell Line, Tumor-
dc.subject.meshCell Proliferation-
dc.subject.meshDacarbazine-
dc.subject.meshDrug Resistance, Neoplasm-
dc.subject.meshGuanine-
dc.subject.meshHumans-
dc.subject.meshMale-
dc.subject.meshMice-
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase-
dc.subject.meshXenograft Model Antitumor Assays-
dc.titleO6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts.en
dc.typeArticleen
dc.contributor.departmentCancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, Manchester M20 9BX, UK.en
dc.identifier.journalBritish Journal of Canceren

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