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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.

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Authors

RICHARD GRUNDY richard.grundy@nottingham.ac.uk
Professor of Paediatric Neuro-Oncology

Kaouthar Bouzinab

Helen Summers

Jihong Zhang

Malcolm F. G. Stevens

Christopher J. Moody

NEIL THOMAS neil.thomas@nottingham.ac.uk
Professor of Medicinal and Biological Chemistry

Marianne B. Ashford

Emily Vitterso

Lisa C. D. Storer



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., …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

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