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Cancer
Cancer is not a single disease but a broad group characterised by malignant cells that are clearly distinguished from normal cells by uncontrolled growth (Workman, 2001). They are caused by abnormalities in the sequence and expression of critical genes, most notably oncogenes and tumour suppressor genes. The language of cancer is to be found in the resulting deregulation of crucial biochemical pathways that control proliferation, the cell cycle, survival/apoptosis, angiogenesis, invasion and metastasis. Aberrant cellular growth is a primary cause in the development of malignant tumours (Suyama et al., 2002). However, additional events take place, which enable tumour cells to invade tissue barriers and metastasise to distant sites. These events include detachment of cells from the primary tumour, the crossing of tissue boundaries, entrance and exit from the circulatory system, the infiltration of distant organs, and the formation of metastatic implants.
Cancer incidences
Cancer has troubled humans throughout recorded history. This disease remains a major public health issue at the beginning of the 21st century (Grella et al., 2003). It is the leading cause of death worldwide (www.who.int, 2005). From a total of 58 million deaths worldwide in 2005, it accounts for 7.6 million (or 13%) of all deaths. That is more than the percentage of deaths caused by HIV/AIDS, tuberculosis and malaria put together (McIntyre, 2007). There are currently 25 million people living with cancer.
Radiotherapy
Approximately 50% of all cancer patients are treated with radiotherapy, either as primary treatment with curative intent or for palliation of cancer related symptoms (Vink et al., 2007). Likelihood of tumour response after radiotherapy is determined by the total radiation dose required for tumour cell kill and varies between tumour types, ranging from very radiosensitive low grade lymphomas (90% tumour control at 4 Gy) to notoriously radioresistant malignant gliomas (not responsive at clinically achievable doses). For patients treated with radiotherapy, fibrosis, necrosis and severe organ dysfunction may appear months to years after treatment accomplishment (Koukourakis and Danielidis, 2005).
Limitations of current cancer treatment
The majority of current cancer drugs are cytotoxic agents that exert their effects on all proliferating cells, both normal and cancerous (Workman, 2001). This is the case even for recently successful drugs such as irinotecan in colorectal cancer, taxanes in breast, ovarian and lung cancer; and carboplatin in ovarian cancer. Since cytotoxic agents have a selectively ‘anti-proliferative’ action rather than selective ‘anti-cancer’ properties, the therapeutic window for tumour versus normal tissue is modest at best and toxic side effects are the norm. Exposure of normal tissues that have a high rate of cellular proliferation (such as bone marrow, gastrointestinal epithelial cells and cells of the hair follicles) to these anti-proliferative drugs leads to major toxicities (Mollinedo and Gajate, 2006). Renal and gastrointestinal toxicity has been reduced considerably in the clinic by intravenous hydration and anti-emetics that antagonise the 5-hydroxytryptamine type 3 receptor (Screnci and McKeage, 1999).
Declaration
Acknowledgements
Dedication
Chapter I.Introduction
1.1 Cancer
1.2 Cancer incidences
1.3 Cancer treatment
1.4 Limitations of current cancer treatment
1.5 The need for new anti-cancer drugs
1.6 Drug design and targets
1.7 Metal based drugs
1.8 Metal phosphines as anti-tumour agents
1.9 Hypothesis
1.10 Aim of study
1.11 Objectives of the study
Chapter II Phosphines and metal phosphine complexes
2.1 Phosphine ligands
2.2 Pyridylphosphines
2.3 Metal pyridylphosphines
2.4 Metal complexes of diphenylphosphine ligands
Chapter III Preparation and characterisation of Pt and Pd phosphine complexes
3.1 Synthesis of metal phenylphosphine complexes
3.2 Synthesis of metal pyridylphosphine complexes
3.3 General discussion on the behaviour of the 2, 3 and 4-pyridylphosphine ligands
3.4 Structural analysis of compounds 3b, 4e 3f, 1h and 2h
Chapter IV Experimental details
4.1 General
4.2 Synthesis of phenyl phosphine complexes
4.3 Preparation of pyridyl phosphine ligands
4.4 Preparation of 2-pyridyl phosphine complexes
4.5 Preparation of 3-pyridyl phosphine complexes
Chapter V Stability, Lipophilicity and Cytotoxicity
5.1 Stability
5.2 Nuclear Magnetic Resonance Spectroscopy (NMR).
5.3 Evaluation of stability of the test compounds by 31 P NMR spectroscopy.
5.4 Materials and methods
5.5 Results
5.6 Lipophilicity
5.7 Aim of the experiment
5.8 Materials and methods
5.9 Results and discussion
5.10 Cytotoxicity
5.11 Determination of cytotoxicity
5.12 Materials and methods
5.13 General procedure
5.14 Statistical analysis
5.15 Results and discussion
Chapter VI Analysis of mitochondrial function
6.1 The Mitochondria
6.2 Mitochondria and cancer
6.3 Mitochondria as cancer drug targets
6.4 Analysis of mitochondrial membrane potential
6.5 Objective of this experiment
6.6 Materials and methods
6.7 Results and discussion
6.8 Plasma membrane Potential.
6.9 Analysis of plasma membrane changes by flow cytometry
6.10 Materials and methods
6.11 Results and discussion
Chapter VII Apoptosis
7.1 Introduction
7.2 Apoptosis and cancer
7.3 Apoptosis and chemotherapy
7.4 Detection of apoptosis by flow cytometry
7.5 Materials and methods
7.6 Results and discussion
Chapter VIII The cell cycle
8.1 Introduction
8.2 Cell cycle and carcinogenesis
8.3 Cell cycle and chemotherapy
8.4 Determination of the effect of Pg 8 and [Au(dppe)2]Cl on cell cycle of Jurkat cells
8.5 Materials and methods
8.6 Results and discussion
Chapter IX Uptake studies
9.1 Introduction
9.2 Preparation of 103 Pd labelled [Pd(d2pyrpe)2][PF6]2
9.3 Preparation of 198 Au labelled [Au(dppe)2]Cl
9.4 Uptake of [103 Pd(d2pyrpe)2][PF6]2 and [198 Au(dppe)2] Cl by Jurkat cells
9.5 Materials and methods
9.6 Results and discussion
9.7 Biodistribution of [103 Pd(d2pyrpe)2][PF6]2 and [198 Au(dppe)2]Cl in rats
9.8 Results and discussion
Chapter X Acute toxicity studies
10.1 Introduction
10.2 Motivation for the study
10.3 Aim
10.4 Materials and Methods
10.5 Results and discussion
Chapter XI Conclusions
