Activity of novel ferronucleosides in pancreatic cancer cells

Rana, Marium (2022). Activity of novel ferronucleosides in pancreatic cancer cells. University of Birmingham. Ph.D.

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with an extremely poor prognosis attributed to late diagnosis and limited therapeutic options. Acquired chemoresistance to drugs such as gemcitabine, used to treat PDAC creates a clinical demand for novel anticancer agents that exhibit similar potency, evade cross resistance, and improve patient outcome. The clinical success of cisplatin has driven interest into metal complexes which has led to the proposal of organometallic compounds as anticancer agents. These compounds, particularly ferrocene-based complexes such as ferrocifen, have shown promising anticancer activity exhibiting different effects to those observed with existing anticancer drugs. As part of their drug discovery work, Tucker et al. synthesised a novel ferronucleoside called TUC-1 which showed promising anticancer activity.
In this work, the anticancer activity of TUC-1 and derivatives is evaluated in a range of pancreatic cancer cell lines compared to established chemotherapeutics supported by TUC-1 evaluation in NCI-60 panel of cancer cell lines. This is followed by investigations into the mechanism of action with an emphasis on DNA replication fork stalling and downstream events. Pre-clinical data evaluating the drug metabolism and pharmacokinetic properties of TUC-1 is also presented. In addition to this, a synergistic relationship is established between TUC-1 and a Chk kinase inhibitor, AZD7762, that is shown to potentiate the effects of TUC-1.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):