In search of effective therapies to overcome resistance to Temozolomide in brain tumours  

作　　者：Kaouthar Bouzinab Helen Summers Jihong Zhang Malcolm F.G.Stevens Christopher J.Moody Lyudmila Turyanska Neil R.Thomas Pavel Gershkovich Marianne B.Ashford Emily Vitterso Lisa C.D.Storer Richard Grundy Tracey D.Bradshaw 

机构地区：[1]School of Pharmacy,University of Nottingham,Nottingham NG72RD,UK [2]School of Chemistry,University of Nottingham,Nottingham NG72RD,UK [3]School of Physics and Astronomy,University of Nottingham,Nottingham NG72RD,UK [4]Advanced Drug Delivery,Pharmaceutical Sciences,R&D,AstraZeneca,Macclesfield SK104TF,UK [5]School of Medicine,Queen’s Medical Centre,University of Nottingham,Nottingham NG72UH,UK.

出　　处：《Cancer Drug Resistance》2019年第4期1018-1031,共14页癌症耐药（英文）

基　　金：This studentship is supported by the Engineering and Physical Sciences Research Council(EP/L01646X).

摘　　要：Glioblastoma multiforme is the most common and lethal brain tumour-type.The current standard of care includes Temozolomide(TMZ)chemotherapy.However,inherent and acquired resistance to TMZ thwart successful treatment.The direct repair protein methylguanine DNA methyltransferase(MGMT)removes the cytotoxic O6-methylguanine(O6-MeG)lesion delivered by TMZ and so its expression by tumours confers TMZ-resistance.DNA mismatch repair(MMR)is essential to process O6-MeG adducts and MMR-deficiency leads to tolerance of lesions,resistance to TMZ and further DNA mutations.In this article,two strategies to overcome TMZ resistance are discussed:(1)synthesis of imidazotetrazine analogues-designed to retain activity in the presence of MGMT or loss of MMR;(2)preparation of imidazotetrazine-nanoparticles to deliver TMZ preferably to the brain and tumour site.Our promising results encourage belief in a future where better prognoses exist for patients diagnosed with this devastating disease.

关 键 词：Brain cancer temozolomide-resistance ANALOGUES drug delivery APOFERRITIN 

分 类 号：R73[医药卫生—肿瘤]