O6-(4-bromothenyl)guanine improves the therapeutic index of temozolomide against A375M melanoma xenografts

✍ Scribed by Mark R. Middleton; Jane Kelly; Nicholas Thatcher; Dorothy J. Donnelly; R. Stanley McElhinney; T. Brian H. McMurry; Joan E. McCormick; Geoffrey P. Margison

• Publisher: John Wiley and Sons
• Year: 2000
• Tongue: French
• Weight: 122 KB
• Volume: 85
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/(sici)1097-0215(20000115)85:2<248::aid-ijc16>3.0.co;2-v

✦ Synopsis

Tumour 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 F 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. Int.