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

Abstract

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, 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 (IC(50) approximately 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 approximately 60%, with extensive recovery by 24 h. PaTrin-2 (10 microM) substantially increased the growth inhibitory effects of temozolomide in MCF-7 cells (D(60)=10 microM with PaTrin-2 vs 400 microM 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.

• Authors: M Clemons, J Kelly, A J Watson, A Howell, R S McElhinney, T B H McMurry, G P Margison
• Journal: British journal of cancer (Br J Cancer) Vol. 93 Issue 10 Pg. 1152-6 (Nov 14 2005) ISSN: 0007-0920 [Print] England
• PMID: 16278661 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• O(6)-(4-bromothenyl)guanine
• Guanine
• Dacarbazine
• O(6)-Methylguanine-DNA Methyltransferase
• Temozolomide

Topics

• Animals
• Body Weight (drug effects)
• Breast Neoplasms (drug therapy, enzymology, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dacarbazine (analogs & derivatives, pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Guanine (analogs & derivatives, pharmacology)
• Humans
• Male
• Mice
• O(6)-Methylguanine-DNA Methyltransferase (metabolism)
• Temozolomide
• Xenograft Model Antitumor Assays