O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts.
dc.contributor.author | Clemons, Mark | |
dc.contributor.author | Kelly, J | |
dc.contributor.author | Watson, Amanda J | |
dc.contributor.author | Howell, Anthony | |
dc.contributor.author | McElhinney, R S | |
dc.contributor.author | McMurry, T B H | |
dc.contributor.author | Margison, Geoffrey P | |
dc.date.accessioned | 2009-08-10T17:25:11Z | |
dc.date.available | 2009-08-10T17:25:11Z | |
dc.date.issued | 2005-11-14 | |
dc.identifier.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 | en |
dc.identifier.issn | 0007-0920 | |
dc.identifier.pmid | 16278661 | |
dc.identifier.doi | 10.1038/sj.bjc.6602833 | |
dc.identifier.uri | http://hdl.handle.net/10541/76854 | |
dc.description.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. | |
dc.language.iso | en | en |
dc.subject | Breast Cancer | en |
dc.subject | Cell Line Tumour | en |
dc.subject.mesh | Animals | |
dc.subject.mesh | Body Weight | |
dc.subject.mesh | Breast Neoplasms | |
dc.subject.mesh | Cell Line, Tumor | |
dc.subject.mesh | Cell Proliferation | |
dc.subject.mesh | Dacarbazine | |
dc.subject.mesh | Drug Resistance, Neoplasm | |
dc.subject.mesh | Guanine | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Male | |
dc.subject.mesh | Mice | |
dc.subject.mesh | O(6)-Methylguanine-DNA Methyltransferase | |
dc.subject.mesh | Xenograft Model Antitumor Assays | |
dc.title | O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts. | en |
dc.type | Article | en |
dc.contributor.department | Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, Manchester M20 9BX, UK. | en |
dc.identifier.journal | British Journal of Cancer | en |
html.description.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. |