O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts

Tumour resistance to chemotherapy involving methylating agents such as DTIC (dacarbazine) and temozolomide is linked to expression of the DNA repair protein O-6-alkylguanine-DNA alkyltransferase (MGMT). There is considerable interest in improving the efficacy of such O-6-alkylating chemotherapy by the prior inactivation of MGMT. We have examined the effect of the modified guanine base, O-6-(4-bromothenyl)guanine (PaTrin-2, Patrin(TM), Lomeguatrib) on MGMT activity and cell or xenograft tumour growth inhibition by temozolomide in the human breast carcinosarcoma cell line, MCF-7. PaTrin-2 effectively inactivated MGMT in MCF-7 cells (IC50 similar to 6 nM) and in xenografts there was complete inactivation of MGMT within 2 h of dosing (20 mg kg(-1) i.p.) and only slight recovery by 24 h. MGMT inactivation in a range of murine host tissues varied between complete and similar to 60%, with extensive recovery by 24 h. PaTrin-2 (10 mu M) substantially increased the growth inhibitory effects of temozolomide in MCF-7 cells (D-60 = 10 mu M with PaTrin-2 vs 400 mu M without). In MCF-7 xenografts, neither temozolomide (100 mg kg(-1) day(-1) for 5 days) nor PaTrin-2 (20 mg kg(-1) day(-1) for 5 days) had any significant effect on tumour growth. In contrast, the PaTrin-2-temozolomide combination produced a substantial tumour growth delay: median tumour quintupling time was increase by 22 days (P < 0.005) without any significant increase in toxicity as assessed from animal weight. A PaTrin-2-temozolomide combination may therefore be beneficial in the treatment of human breast cancers.