Beirne, Darren (2024) Combination chemotherapy: a modern approach to target cancer with dual-action Tyrosine Kinase inhibitor-Platinum based drugs. PhD thesis, National University of Ireland Maynooth.
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DFB Final Thesis Combined 10-02-2025.pdf
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Abstract
Platinum complexes as anticancer drugs (i.e. cisplatin, carboplatin, oxalilplatin) were
discovered decades ago and have been approved and are worldwide used to treat a
variety of tumours. Their activity is limited by dose-dependent side effects (nephro-,
neuro- and ototoxicity) and the lack of selectivity toward cancer tissue with respect to
healthy cells remains one of the major drawbacks. Combination chemotherapy is a
burgeoning strategy that consists of combining in the same molecule two different drugs
with two different mechanisms of action that can operate simultaneously, targeting
different features on the cancer cell. Tyrosine kinases (TK) are promising targets in
oncology and play a major role in cell regulation pathways (e.g. metabolism,
transcription, cell division and programmed cell death) and TK deregulation is often
related to cancer onset. Currently, the activity of platinum-based drugs against certain
tumours, is limited because resistance is often acquired after few chemotherapeutic
cycles. The aim of this project is to exploit the combination chemotherapy strategy to
develop new drugs that will target cancer, combining in one unique molecule, the DNA
damaging activity of platinum with TK inhibitors. Imatinib, Nilotinib and Sunitinib are
known TKs inhibitors that are FDA approved to treat solid tumors, such as
gastrointestinal stromal cancer and renal cell carcinoma. The two active components
(platinum(II) and TK inhibitor) are released simultaneously upon intracellular reduction
or hydrolysis, and work in cooperation to increase the overall anticancer efficacy.
Item Type: | Thesis (PhD) |
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Keywords: | Combination chemotherapy; modern approach; cancer; dual-action Tyrosine Kinase inhibitor-Platinum; |
Academic Unit: | Faculty of Science and Engineering > Chemistry |
Item ID: | 19639 |
Depositing User: | IR eTheses |
Date Deposited: | 03 Apr 2025 13:58 |
Funders: | Research Ireland |
URI: | https://mural.maynoothuniversity.ie/id/eprint/19639 |
Use Licence: | This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here |
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