Shepherd, S.L. (2018) Pre-clinical Evaluation of Novel Inorganic Compounds as Potential Anticancer Therapies. Doctoral thesis, University of Huddersfield.

Background: Recent developments in our understanding of the biology of cancer has provided the opportunity to develop targeted agents with more specific pharmacological activity against cancer cells. Despite this shift toward targeted drug discovery, the much hoped-for paradigm shift in cancer treatment has not been realised. Tumour heterogeneity, plasticity and genomic instability are issues that contribute to this problem. One approach to circumvent these issues is to adopt a phenotypic based approach to drug evaluation where compounds with multiple mechanisms of action leading to a desirable phenotypic effect can be identified. The challenge with such an approach is to retain selectivity toward cancer cells as opposed to non-cancer cells.

Aims: The aim of this study is to apply a phenotype based drug evaluation program that incorporates a measure of selectivity to the preclinical evaluation of a series of novel organometallic complexes.

Methods: In this study, a series of novel inorganic complexes were evaluated against cancer and non-cancer cell lines. The primary evaluation procedures involved chemosensitivity testing with compounds being selected for further studies based upon (i) potency (ii) an in vitro selectivity index (SI) defined as the IC50 for non-cancer cells divided by the IC50 for cancer cells and (iii) comparable or improved properties than cisplatin, oxaliplatin and carboplatin with respect to potency and selectivity. Those compounds that met the selection criteria were evaluated further with the initial aim of characterising key pharmacological events such as cell cycle effects and induction of apoptosis.

Results and Discussion: Initial studies focused on the clinically approved platinum based with cisplatin and oxaliplatin being significantly more potent than carboplatin. Selectivity for cancer over non-cancer cells was observed with selectivity index (SI) values typically in the range of 0.85-9.71, 0.36-3.35 and 2.18-7.44 for cisplatin, oxaliplatin and carboplatin respectively. A total of 210 test compounds were evaluated in this thesis and of these, a total of 91 compounds exhibited potency values equal to or better than the platinates. In contrast however, only 64 compounds had superior SI values compared to platinates. Of these, the most promising compounds were a series of large molecular weight metallohelicates that exhibited potency (in the nM range) and SI values up to a maximum of 93 (nearly 28 times higher than the best performing platinum drug). Analysis of these compounds demonstrated that they do not induce apoptosis, but preliminary data suggests that they induce an autophagic death response.

Conclusions: The results of this study have demonstrated that a phenotypic based drug evaluation process based upon potency and selectivity in vitro is capable of identifying novel chemical entities with promising properties. This screen has more discriminatory power than potency alone and the concept of an 'in vitro selectivity index' has proved valuable in identifying a series of novel metallohelicate compounds as potential anti-cancer drugs. Significant further work is required to identify their mechanism(s) of action and pharmacological properties but their potential ability to induce autophagic cell death over apoptosis is of interest.

Samantha Shepherd FINAL THESIS.PDF - Accepted Version
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