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

Grundy, Richard; 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.; Bradshaw, Tracey D.

Abstract

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.

Citation

Grundy, R., Bouzinab, K., Summers, H., Zhang, J., Stevens, M. F. G., Moody, C. J., Turyanska, L., Thomas, N. R., Gershkovich, P., Ashford, M. B., Vitterso, E., Storer, L. C. D., & Bradshaw, T. D. (2019). In search of effective therapies to overcome resistance to Temozolomide in brain tumours. Cancer Drug Resistance, 2(4), 1018-1031. https://doi.org/10.20517/cdr.2019.64

• Journal Article Type: Article
• Acceptance Date: Sep 28, 2019
• Online Publication Date: Oct 13, 2019
• Publication Date: Oct 19, 2019
• Deposit Date: Nov 26, 2019
• Publicly Available Date: Nov 26, 2019
• Journal: Cancer Drug Resistance
• Electronic ISSN: 2578-532X
• Publisher: OAE Publishing
• Peer Reviewed: Peer Reviewed
• Volume: 2
• Issue: 4
• Pages: 1018-1031
• DOI: https://doi.org/10.20517/cdr.2019.64
• Public URL: https://nottingham-repository.worktribe.com/output/2888319
• Publisher URL: https://cdrjournal.com/article/view/3234
• Contract Date: Nov 26, 2019