O(6)-(4-bromothenyl)guanine improves the therapeutic index of temozolomide against A375M melanoma xenografts.
AuthorsMiddleton, Mark R
Donnelly, Dorothy J
McElhinney, R S
McMurry, T B
McCormick, J E
Margison, Geoffrey P
AffiliationCancer Research Campaign Department of Carcinogenesis, Paterson Institute for Cancer Research, Manchester, UK. firstname.lastname@example.org
MetadataShow full item record
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.
CitationO(6)-(4-bromothenyl)guanine improves the therapeutic index of temozolomide against A375M melanoma xenografts. 2000, 85 (2):248-52 Int J Cancer
JournalInternational Journal of Cancer
- Effect of O6-(4-bromothenyl)guanine on different temozolomide schedules in a human melanoma xenograft model.
- Authors: Middleton MR, Thatcher N, McMurry TB, McElhinney RS, Donnelly DJ, Margison GP
- Issue date: 2002 Aug 10
- 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
- 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
- Thresholds of O6-alkylguanine-DNA alkyltransferase which confer significant resistance of human glial tumor xenografts to treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea or temozolomide.
- Authors: Kokkinakis DM, Bocangel DB, Schold SC, Moschel RC, Pegg AE
- Issue date: 2001 Feb
- Effect of single and multiple administration of an O6-benzylguanine/temozolomide combination: an evaluation in a human melanoma xenograft model.
- Authors: Wedge SR, Porteous JK, Newlands ES
- Issue date: 1997