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• W108306279 abstract "Conventional chemotherapeutic drugs target proliferating cells, as a result normalnproliferating cells are also targeted by these drugs resulting in a number ofnunwanted side-effects and toxicities. Cancer has been described as a disease ofnthe cell cycle, as many of the genes mutated in the process of oncogenesis are cellncycle control genes, for example p53, Rb, and ATM. Many of these genes areninvolved in cell cycle checkpoint mechanisms, which respond to cellular insultsnsuch as DNA damage, replication errors, and external stress, by delaying cell cyclenprogression. This delay gives the cell time to assess the damage and undertakenrepair, or if the damage is to severe then initiation of apoptosis may occur. Thenloss of checkpoints in cancer cells provides them with a growth advantage, but it isnalso a weakness as they are no longer be able to respond correctly to cellularninsults. Therefore identifying checkpoints that are commonly lost in a wide rangenof tumour cells and developing chemotherapeutics that selectively target these lostncheckpoints may provide a means of producing more potent anti-cancer drugs thatnhave few side effects than current treatments.n n To assess the validity of this hypothesis, two different approaches werenundertaken. The first involved the detailed analysis of the mode of action of a newnclass of chemotherapeutic agents known as histone deacetylase inhibitors (HDIs).nThese compounds have been shown to be selectively cytotoxic towards a range ofntumour cell types, while remaining relatively non-toxic toward normal cells. Innaddition, these drugs are currently being used in phase I and II clinical trials, yetnthe anti-tumour action of these drugs is unknown.n n This HDI-resistance in normal cells correlates with the induction of a specific G2ncell cycle checkpoint, which is defective in tumour cell lines. The consequence of losing this G2 checkpoint is that sensitive cells progress through an aberrantnmitosis, resulting in apoptosis. In addition, HDI-treatment of non-proliferatingntumour cells also resulted in cell death, indicating the possible use of thesencompounds for treating tumours with a low mitotic index. However, HDI-treatmentndirectly induced the upregulation of the cyclin dependent kinase inhibitornp21waf1/Cip1 in the majority of sensitive tumour cell lines tested. This upregulationnhindered apoptosis increasing resistance to HDI-induced cell death, compared tonhypersensitive cell lines which did not upregulated p21.n n The second approach was to characterise a checkpoint pathway that is defective inna high proportion of tumour cells, with the hope that new drug targets can benidentified. To do this I have utilised previous research from this laboratory whichndemonstrated that treatment with sub-erythemal doses of ultraviolet radiationn(UVR), resulted in an upregulation of the melanoma susceptibility gene productnp16INK4A basal and supra-basal layers of the skin. The upregulation of p16ncorrelated with a p53 independent G2 arrest in these cells, which is also observednin epidermal derived cell lines, while cells that do not contain functional p16 fail tonarrest in G2 in response to low-dose UVR. Furthermore the majority of melanomancell lines have either lost or contain non-functional p16. In addition, p16 isnassociated with an increased risk of melanoma predisposition, and loss of pi6nexpression correlates with more aggressive and invasive melanoma tumours.n" @default.
• W108306279 created "2016-06-24" @default.
• W108306279 creator A5043907665 @default.
• W108306279 date "2004-01-01" @default.
• W108306279 modified "2023-09-27" @default.
• W108306279 title "Targeting cell cycle checkpoints to specifically kill cancer" @default.
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