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

• Published in: Cancer drug resistance Vol. 2; no. 4; pp. 1018 - 1031
• Main Authors: Bouzinab, Kaouthar, Summers, Helen, Zhang, Jihong, Stevens, Malcolm F G, Moody, Christopher J, Turyanska, Lyudmila, Thomas, Neil R, Gershkovich, Pavel, Ashford, Marianne B, Vitterso, Emily, Storer, Lisa C D, Grundy, Richard, Bradshaw, Tracey D
• Format: Journal Article
• Language: English
• Published: United States OAE Publishing Inc 01.01.2019
• Subjects: Review; analogues; drug delivery; apoferritin; Brain cancer; temozolomide-resistance
• ISSN: 2578-532X
• DOI: 10.20517/cdr.2019.64

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 -methylguanine ( 6-MeG) lesion delivered by TMZ and so its expression by tumours confers TMZ-resistance. DNA mismatch repair (MMR) is essential to process 6-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.