O-6-(4-bromothenyl)guanine improves the therapeutic index of temozolomide against A375M melanoma xenografts

Tumour resistance to methylating agents is linked to expression of the DNA repair protein O-6-alkylguanine-DNA alkyltransferase (ATase), There is cons iderable interest in improving the efficacy of O-6-alkylating chemotherapy by prior depletion of ATase, We have tested the ability of a modified guani ne base, O-6-(4-bromothenyl)guanine (4BTG), to inactivate ATase and to enha nce the anti-tumour effect of temozo-lomide in an animal model system. A375 M human melanoma xenografts were established in the flanks of nude mice. AT ase depletion after a single dose of 4BTG or O-6-BG (20 mg/kg i.p.) was det ermined 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-d ay schedule on tumour growth. 4BTG was an effective inactivator of ATase in tumour, producing complete depletion within 2 hr of dosing, Furthermore, i t enhanced the tumour growth delay achieved with temozolomide, increasing t he tumour quintupling time by 8.7 days (95% confidence interval 6.1-11.3 da ys, p < 0.0001). Whilst the delay in tumour growth was indistinguishable fr om 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 ATas e and enhances the therapeutic ratio of temozolomide in this model system t o a greater extent than O-6-BG. Int. J. Cancer 85:248-252,2000. (C) 2000 Wi ley-Liss, Inc.