Dinuclear Platinum Complexes as potential anticancer drugs : insights
in the intracellular distribution
Kalayda, G.V.
Citation
Kalayda, G. V. (2006, February 1). Dinuclear Platinum Complexes as potential anticancer
drugs : insights in the intracellular distribution. Retrieved from
https://hdl.handle.net/1887/4283
Version:
Corrected Publisher’s Version
License:
Licence agreement concerning inclusion of doctoral thesis in the
Institutional Repository of the University of Leiden
Downloaded from:
https://hdl.handle.net/1887/4283
people around the planet were diagnosed with cancer in 2000, and 6 million died from it. And these numbers are growing. With an ageing population, the spread of western-style diets, and increasing tobacco consumption, cancer is on the rise around the globe. In United States of America, for example, projections suggest that 40% of those alive today will be diagnosed with some form of cancer at some point in their lives. By 2010, that number will have climbed to 50%.
Cancer is characterized by uncontrolled cell growth. Healthy cells regulate their division into daughter cells carefully, subordinating their own Darwinian tendency to reproduce in favor of the survival of the body they inhabit. It is one of the marvels of evolution that they are able to do this, and so allow the development of multicellular creatures. But evolution works on many levels, and it is almost inevitable that mutations in some of the trillions of cells that make up a human body will disable the regulatory genes. Then it is just a matter of the survival of the fittest among cells. In a competition between regulated and unregulated cells, the unregulated ones will multiply faster, and win. The result is cancer.
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Contents
List of abbreviations
Chapter 1. Introduction
1.1. General introduction
1.2. Cisplatin: mechanism of action 1.3. Cellular uptake and distribution of platinum antitumor drugs 1.4. Mechanisms of cisplatin nephrotoxicity
1.5. Cisplatin resistance
1.6. New platinum anticancer compounds
1.7. Polynuclear platinum complexes as potential anticancer drugs 1.8. Drug targeting to the therapeutic sites 1.9. Aim and scope of this thesis
Chapter 2. Synthesis and anticancer activity of the new azine-bridged dinuclear platinum(II) complexes
Chapter 3. Dinuclear platinum complexes with fluorescent anthraquinones: cellular processing in A2780 human ovarian carcinoma cells
Chapter 4. Dinuclear platinum anticancer complexes with fluorescent anthraquinones: cellular processing in U2-OS human osteosarcoma cells
Chapter 5. Fluorescent labelled dinuclear platinum complexes as a tool for investigating the cellular pathways of dinuclear platinum anticancer drugs
Chapter 6. Application of dinuclear platinum complexes in drug targeting
Chapter 7. Structure-toxicity relationships for different types of dinuclear platinum complexes
Chapter 8. Summary, conclusions and future perspectives 8.1. Introduction
8.2. Summary
8.3. Conclusions and future perspectives
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List of abbreviations
DNA deoxyribonucleic acid RNA ribonucleic acid
GSH glutathione
NER nucleotide excision repair HM G high mobility group
NM R nuclear magnetic resonance ATP adenosinetriphosphate
M T metallothionein
M RP multidrug resistance protein(s) M M R mismatch repair
A2780 human ovarian carcinoma cell line
A2780cisR cisplatin-resistant human ovarian carcinoma cell line U2-OS human osteosarcoma cell line
U2-OS/Pt cisplatin-resistant human osteosarcoma cell line L1210/0 murine leukemia cell line
L1210/DDP cisplatin-resistant murine leukemia cell line dien diethylenetriamine
L-BSO L-buthionine-S,R-sulfoximine
NBD C6-ceramide 6-((N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)hexanoyl)-sphingosine
CFDA carboxyfluorescein diacetate
DNP dinitrophenyl Boc tert-butyloxycarbonyl ta 1,2,3-triazolate pz pyrazolate pzn pyrazine pmn pyrimidine pdn pyridazine 2,5pzn 2,5-dimethylpyrazine qzn quinazoline pht phthalazine 9EtG 9-ethylguanine GM P 5’-guanosinemonophosphate
TSP 3-(trimethylsilyl)propionic acid-d4, sodium salt DM F (dmf) dimethylformamide (as a ligand)
s singlet d doublet t triplet m multiplet δ chemical shift h hour(s) min minute(s)
IC50 drug concentration that inhibits cell growth for 50% with respect to control
MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide
PBS phosphate buffered saline
ptx pentoxyfilline
TEAA triethylammonium acetate ULS Universal Linkage System SDS sodium dodecyl sulfate
ICP-OES inductively coupled plasma optical emission spectrometer TEER transepithelial electrical resistance
ESI electrospray ionization
HPLC high performance liquid chromatography
SE succinimidyl ester
DCC dicyclohexylcarbodiimide SuOH N-hydroxysuccinimide
LC ESI-MS liquid chromatography coupled to electrospray ionization mass spectrometry
OCT organic cation transporter(s)
EPR (effect) enhanced permeability and retention (effect) ADEPT antibody-directed enzyme prodrug therapy DMEM Dulbecco’s modified Eagle’s medium
