Next-generation Temozolomide: Repair Resistance DNA-Targeted Anti-cancer Agents with Broader Spectrum Activity.

Three novel TMZ analogues that possess in vitro anti-tumour activity superior to TMZ in GBM and colorectal carcinoma v

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Background.

Glioblastoma multiforme (GBM; grade IV astrocytoma) is the most prevalent and aggressive adult primary brain tumour. Standard of care includes surgery, radiotherapy and adjuvant cytotoxic therapy temozolomide (TMZ), conferring a median survival me of 14.6 months. The therapeutic benefit of TMZ depends on its ability to damage DNA and trigger the death of tumour cells. Although TMZ offers some hope to GBM patients, a best 5- year survival rate of 9.8% is achieved.

A key limitation of TMZ is the repair of TMZ-induced DNA damage by the DNA damage repair protein methylguanine-DNA methyl transferase (MGMT) or by deficient mismatch repair (MMR) which are associated with inherent and acquired resistance to TMZ treatment. This not only limits effective therapy in the majority of GBM patients (~47%) but also restricts TMZ’s utility to a very small number of other tumour-types.

University of Nottingham researchers have enhanced this, by synthesised three novel N3-propargyl, C8-substuted TMZ analogues which overcome MGMT+/MMR resistance and possess in vitro an-tumour activity superior to TMZ in GBM and colorectal carcinoma (CRC) cell lines. DMPK package expected autumn 2017.

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