Effect of O6-(4-bromothenyl)guanine on different temozolomide schedules in a human melanoma xenograft model.
AuthorsMiddleton, Mark R
McMurry, T Brian H
McElhinney, R Stanley
Donnelly, Dorothy J
Margison, Geoffrey P
AffiliationCancer Research UK, Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, United Kingdom.
MetadataShow full item record
AbstractThe DNA repair protein O(6)-alkylguanine DNA alkyltransferase (ATase) is a major component of resistance to treatment with methylating agents and nitrosoureas. Inactivation of the protein, via the administration of pseudosubstrates, prior to chemotherapy has been shown to improve the latter's therapeutic index in animal models of human tumours. We have also shown that rational scheduling of temozolomide, so that drug is administered at the ATase nadir after the preceding dose, increases tumour growth delay in these models. We now report the results of combining these two approaches. Nude mice bearing A375M human melanoma xenografts were treated with vehicle or 100 mg/kg temozolomide ip for 5 doses spaced 4, 12 or 24 hr apart. Each dose was preceded by the injection of vehicle or 20 mg/kg 4BTG. All treatments resulted in significant delays in tumour quintupling time compared with controls: by 6.2, 5.9 and 16.8 days, respectively, for 24-, 12- and 4-hourly temozolomide alone and by 22.3, 21.3 and 22.1 days, respectively, in combination with 4BTG. Weight loss due to TMZ was unaffected by the presence of 4BTG. This was of the order of 6.2-10.6% with 24- and 12-hourly administration and 17.4-20.1% (p < 0.0001) with 4-hourly treatment. In our model, combining daily temozolomide with 4-BTG confers increased antitumour activity equivalent to that achieved by compressing the temozolomide schedule but with less toxicity. Using temozolomide schedule compression with 4-BTG does not improve on this result, suggesting that ATase inactivation with pseudosubstrates is a more promising means of enhancing the activity of temozolomide than compressed scheduling.
CitationEffect of O6-(4-bromothenyl)guanine on different temozolomide schedules in a human melanoma xenograft model. 2002, 100 (5):615-7 Int. J. Cancer
JournalInternational Journal of Cancer
- O(6)-(4-bromothenyl)guanine improves the therapeutic index of temozolomide against A375M melanoma xenografts.
- Authors: Middleton MR, Kelly J, Thatcher N, Donnelly DJ, McElhinney RS, McMurry TB, McCormick JE, Margison GP
- Issue date: 2000 Jan 15
- Four-hourly scheduling of temozolomide improves tumour growth delay but not therapeutic index in A375M melanoma xenografts.
- Authors: Middleton MR, Kelly J, Goodger S, Thatcher N, Margison GP
- Issue date: 2000
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- O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts.
- Authors: Clemons M, Kelly J, Watson AJ, Howell A, McElhinney RS, McMurry TB, Margison GP
- Issue date: 2005 Nov 14