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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.
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
html.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.


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