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dc.contributor.authorMiddleton, Mark R
dc.contributor.authorKelly, Jane
dc.contributor.authorThatcher, Nick
dc.contributor.authorDonnelly, Dorothy J
dc.contributor.authorMcElhinney, R S
dc.contributor.authorMcMurry, T B
dc.contributor.authorMcCormick, J E
dc.contributor.authorMargison, Geoffrey P
dc.date.accessioned2010-07-22T09:13:31Z
dc.date.available2010-07-22T09:13:31Z
dc.date.issued2000-01-15
dc.identifier.citationO(6)-(4-bromothenyl)guanine improves the therapeutic index of temozolomide against A375M melanoma xenografts. 2000, 85 (2):248-52 Int J Canceren
dc.identifier.issn0020-7136
dc.identifier.pmid10629085
dc.identifier.urihttp://hdl.handle.net/10541/108144
dc.description.abstractTumour resistance to methylating agents is linked to expression of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (ATase). There is considerable interest in improving the efficacy of O(6)-alkylating chemotherapy by prior depletion of ATase. We have tested the ability of a modified guanine base, O(6)-(4-bromothenyl)guanine (4BTG), to inactivate ATase and to enhance the anti-tumour effect of temozolomide in an animal model system. A375M human melanoma xenografts were established in the flanks of nude mice. ATase depletion after a single dose of 4BTG or O(6)-BG (20 mg/kg i.p.) was determined over a 24 hr period. Subsequently, we tested the effect of 4BTG (20 mg/kg i.p. daily) and/or temozolomide (80-175 mg/kg i.p. daily) over a 5-day schedule on tumour growth. 4BTG was an effective inactivator of ATase in tumour, producing complete depletion within 2 hr of dosing. Furthermore, it enhanced the tumour growth delay achieved with temozolomide, increasing the tumour quintupling time by 8.7 days (95% confidence interval 6.1-11.3 days, p < 0.0001). Whilst the delay in tumour growth was indistinguishable from that observed with O(6)-benzylguanine (O(6)-BG) and temozolomide, the 4BTG combination resulted in considerably less toxicity (0/9 vs. 2/9 deaths; 6.84% weight loss vs. 9.48%, p = 0.019). 4BTG is a potent inactivator of ATase and enhances the therapeutic ratio of temozolomide in this model system to a greater extent than O(6)-BG.
dc.language.isoenen
dc.subjectCancer Transplantationen
dc.subject.meshAdenosine Triphosphatases
dc.subject.meshAnimals
dc.subject.meshAntineoplastic Agents, Alkylating
dc.subject.meshAntineoplastic Combined Chemotherapy Protocols
dc.subject.meshDacarbazine
dc.subject.meshDrug Synergism
dc.subject.meshEnzyme Inhibitors
dc.subject.meshGuanine
dc.subject.meshMale
dc.subject.meshMelanoma
dc.subject.meshMice
dc.subject.meshMice, Nude
dc.subject.meshNeoplasm Transplantation
dc.subject.meshTransplantation, Heterologous
dc.titleO(6)-(4-bromothenyl)guanine improves the therapeutic index of temozolomide against A375M melanoma xenografts.en
dc.typeArticleen
dc.contributor.departmentCancer Research Campaign Department of Carcinogenesis, Paterson Institute for Cancer Research, Manchester, UK. mmiddleton@picr.man.ac.uken
dc.identifier.journalInternational Journal of Canceren
html.description.abstractTumour resistance to methylating agents is linked to expression of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (ATase). There is considerable interest in improving the efficacy of O(6)-alkylating chemotherapy by prior depletion of ATase. We have tested the ability of a modified guanine base, O(6)-(4-bromothenyl)guanine (4BTG), to inactivate ATase and to enhance the anti-tumour effect of temozolomide in an animal model system. A375M human melanoma xenografts were established in the flanks of nude mice. ATase depletion after a single dose of 4BTG or O(6)-BG (20 mg/kg i.p.) was determined over a 24 hr period. Subsequently, we tested the effect of 4BTG (20 mg/kg i.p. daily) and/or temozolomide (80-175 mg/kg i.p. daily) over a 5-day schedule on tumour growth. 4BTG was an effective inactivator of ATase in tumour, producing complete depletion within 2 hr of dosing. Furthermore, it enhanced the tumour growth delay achieved with temozolomide, increasing the tumour quintupling time by 8.7 days (95% confidence interval 6.1-11.3 days, p < 0.0001). Whilst the delay in tumour growth was indistinguishable from that observed with O(6)-benzylguanine (O(6)-BG) and temozolomide, the 4BTG combination resulted in considerably less toxicity (0/9 vs. 2/9 deaths; 6.84% weight loss vs. 9.48%, p = 0.019). 4BTG is a potent inactivator of ATase and enhances the therapeutic ratio of temozolomide in this model system to a greater extent than O(6)-BG.


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