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

Bradshaw, Tracey D.

Authors

Tracey D. Bradshaw



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.

Journal Article Type Article
Publication Date Oct 13, 2019
Journal Cancer Drug Resistance
Electronic ISSN 2578-532X
Publisher OAE Publishing
Peer Reviewed Peer Reviewed
Volume 2
APA6 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, https://doi.org/10.20517/cdr.2019.64
DOI https://doi.org/10.20517/cdr.2019.64
Publisher URL https://cdrjournal.com/article/view/3234

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