No description available.

The abundant nuclear enzyme poly (ADP-ribose)polymerase (P ARP) catalyses the formation of long homopolymeric chains of ADP-ribose, utilising NAD+ as a substrate, as the immediate cellular response to DNA damage. PARP recognises a damaged section of DNA and initiates polymer synthesis, which is believed to act as a signal to effect the repair of the lesion. A selective, potent PARP inhibitor could block the recognition, and hence repair, of DNA damage induced by cancer chemotherapy. Since increased DNA repair is regarded as a mechanism whereby tumour cells can become resistant to treatment, PARP inhibitors have therapeutic potential as resistance modifying agents. From a study of PARP inhibitors such as 3-hydroxybenzarnide (A), benzimidazole derivatives (B) were proposed as inhibitors of the enzyme, and the synthesis and biological evaluation of a series of such molecules has been achieved. Substituted 2-aryl benzirnidazoles have proved to be highly potent PARP inhibitors (B;R= 4'NO2Ph, IC5o= 59 nM), under a permeabilised cell assay the nitro phenyl derivative (B; R= 4'N02Ph) is the most potent compound reported to date (IC50= 19 nM). 2-Methyl benzirnidazole-4-carboxamide (B; R= Me) has been shown to potentiate the in vitro cytotoxicity of the antitumour agent temozolomide in L1210 cells, and the synthesis of benzimidazole inhibitors suitable for pre-clinical in vivo eluation has also been investigated, This thesis demonstrates that benzimidazole PARP inhibitors have promising potential for clinical development as resistance modifying agents.

Doctor of Philosophy(PhD) / The present study deals with the synthesis, characterization, determination of anticancer activity of three mononuclear trans-planaraminepalladium(II) complexes code named TH5, TH6 and TH7 and three trinuclear complexes code named TH1, TH8 and TH14. The activity of the compounds against human cancer cell lines: A2780, A2780cisR and A2780ZD0473R, cell uptake, DNA-binding and nature of interaction with pBR322 plasmid DNA have been determined. Whereas cisplatin binds with DNA forming mainly intrastrand GG adduct that causes local bending of a DNA strand, TH5, TH6, TH7, TH1 and TH8 bind with DNA forming mainly interstrand GG adducts that causes more of a global change in DNA conformation. Although TH5, TH6 and TH7 each have two substituted pyridine ligands in a trans-geometry (3-hydroxypyridine in TH5, 2-hydroxypyridine in TH6 and 4-hydroxypyridine in TH7), the compounds differ in their activity against ovarian cancer cell lines, indicating that non-covalent interactions involving the hydroxyl group may be playing a significant role in activity of the compounds. Among trinuclear complexes TH1 is found to be significantly more active than cisplatin. It is actually twice as active as cisplatin against the parent cell line A2780, thirteen times as active as cisplatin against the cisplatin-resistant cell line A2780cisR and 11.5 times as active as cisplatin against the cell line A2780ZD0473R. Whereas the resistance factor for cisplatin as applied to the cell lines A2780 and A2780cisR cell lines is 12.9 that for TH1 is 1.98. The results suggest that TH1 has been able to significantly overcome resistance operating in A2780cisR cell line. The compound is soluble in water so that it may be taken orally. Provided it has favourable toxicity profile, TH1 has the potential to be developed into a highly active anticancer drug with a wider spectrum of activity than cisplatin. Although platinum drugs use a shot-gun approach to kill cancerous cells, widespread use in the clinic and increasing volume of their sale indicate that even in the genomic age, there is still need for shot-gun drugs in the clinic.

No description available.

No description available.

No / Telomerase-targeted strategies have aroused recent interest in anti-cancer chemotherapy, because DNA-binding drugs can interact with high-order tetraplex rather than double-stranded (duplex) DNA targets in tumour cells. However, the protracted cell-drug exposure times necessary for clinical application require that telomerase inhibitory efficacy must be accompanied by both low inherent cytotoxicity and the absence of mutagenicity/genotoxicity. For the first time, the genotoxicity of a number of structurally diverse DNA-interactive telomerase inhibitors is examined in the Ames test using six Salmonella typhimurium bacterial strains (TA1535, TA1537, TA1538, TA98, TA100, and TA102). DNA damage induced by each agent was also assessed using the Comet assay with human lymphocytes. The two assay procedures revealed markedly different genotoxicity profiles that are likely to reflect differences in metabolism and/or DNA repair between bacterial and mammalian cells. The mutational spectrum for a biologically active fluorenone derivative, shown to be mutagenic in the TA100 strain, was characterised using a novel and rapid assay method based upon PCR amplification of a fragment of the hisG46 allele, followed by RFLP analysis. Preliminary analysis indicates that the majority (84%) of mutations induced by this compound are C→A transversions at position 2 of the missense proline codon of the hisG46 allele. However, despite its genotoxic bacterial profile, this fluorenone agent gave a negative response in the Comet assay, and demonstrates how unwanted systemic effects (e.g., cytotoxicity and genotoxicity) can be prevented or ameliorated through suitable molecular fine-tuning of a candidate drug in targeted human tumour cells. / CAEB, Balearic Islands and Yorkshire Cancer Research

Owing to their non-selective nature, anti-cancer drugs affect both cancerous and non-cancerous cells and present a major health risk to healthcare staff working with them. This project was conducted at Derriford Hospital, Plymouth, to investigate the extent of contamination with anti-cancer drugs on work surfaces and the environmental emissions of these drugs. In the Isolator study, surface contamination arising from the preparation of five anticancer drug infusions (epirubicin, fluorouracil, cisplatin, oxaliplatin and carboplatin) in a pharmaceutical isolator and external surfaces of infusion bags and syringes using a conventional syringe and needle technique was investigated and compared with that obtained using a closed system drug transfer device (Tevadaptor). Wipe samples were taken for a period of one week from pre-defined areas in a pharmaceutical isolator and from the surface of prepared Intra-Venous (IV) infusion bags and pre-filled syringes to obtain baseline data. Gloves and preparation mats used during this period were also collected. Following a one-week operator familiarisation period, the Tevadaptor device was then introduced for cytotoxic preparation and wipe-sampling of surfaces and collection of consumables was continued for a further week (intervention period). The samples obtained were then analysed by HPLC and ICP-MS. The baseline contamination data from Tevadaptor isolator study was undetected to 0.9 ng cm-2 (epirubicin), undetected to 3.58 ng cm-2 (5-FU) and 0.05-0.92 ng cm-2 (Pt) in the wipe samples from the pharmaceutical isolator surfaces; amounts on glove samples were 1100-6100 ng/glove (epirubicin), 300-8100 ng/glove (5-FU) and 1-6 ng/glove (platinum). During the intervention phase isolator surface contamination was not detected in all samples for 5-FU and epirubicin and platinum was detected on the isolator surfaces in the range of 0.002-0.09 ng cm-2. The use of Tevadaptor resulted in a reduction of contamination on external surfaces by a factor of 10 or more for all marker drugs. A ward study investigated the surface contamination in the oncology out-patient department caused by cisplatin, oxaliplatin, carboplatin and gemcitabine. The study compared the effect of using the Tevadaptor to prepare and administer anticancer drugs infusions on ward surface contamination to the current UK standard practice. A questionnaire was also distributed to participating staff members to assess the user-friendliness of Tevadaptor. Wipe samples were taken from pre-defined areas from the oncology out-patients department and gloves used by nursing staff for assembly and administration of the above drugs were also collected. Sample collection followed a similar schedule to the Tevadaptor isolator study. The baseline ward surface contamination ranged from undetected to 4.97 ng cm-2 (gemcitabine) and 3.1 ng cm-2 (platinum). In the case of gloves used by nursing staff the levels of contamination ranged from undetected to 1251 ng/glove (gemcitabine) and 405.4 ng/glove (platinum). The contamination on ward surfaces during the intervention phase ranged from undetected to 3.21 ng cm-2 (gemcitabine) and 2.69 ng cm-2 (platinum) and contamination levels on gloves ranged from undetected to 9252 ng/glove (gemcitabine) and 1319 ng/glove (platinum). During the intervention phase there was a reduction in frequency of contamination, even though the total amount of surface contamination by anticancer drugs did not always decrease in comparison to baseline data, presumably due to unaccounted spillages. A drain study investigated the presence of platinum in hospital wastewater as a measure of contamination caused by the excretion of platinum-based anticancer drugs by patients. Platinum was measured over a three week period in one of the main drains and in the effluent of the oncology ward. The study showed the presence of measurable quantity of platinum which ranged from 0.02 to 140 μg L-1 in the oncology effluent and 0.03 to 100 μg L-1 in the main drain. Data from this study was coupled with published measurements on the removal of the drugs by conventional sewage treatment and then concentration of platinum arising from each drug was predicted in recipient surface waters as a function of water flow rate. Although predicted concentrations were below EMEA guidelines warranting further risk assessment, the presence of potentially carcinogenic, mutagenic and teratogenic substances in surface waters is cause for concern. The results showed that a closed system drug transfer device (CSTD) used in conjunction with an isolator is highly efficient in reducing surface contamination with anti-cancer drugs. However, despite current best practice contamination on ward surfaces remained even after the use of a CSTD. Nursing as well as healthcare staff should be educated of these results and the risks of occupational exposure to low levels of anti-cancer drugs and the use of PPE should be emphasised. Results of the drain study form the basis of preliminary estimates of the likely concentrations of platinum-based drugs in surface waters and their potential environmental impacts.

The overall aim of the research is to develop a computational platform based on HINT paradigm for manipulating, predicting and analyzing biomacromolecular-ligand structure. A second synergistic goal is to apply the above methodology to design novel and potent anti-cancer agents. The crucial role of the microtubule in cell division has identified tubulin as an interesting target for the development of therapeutics for cancer. Pyrrole-containing molecules derived from nature have proven to be particularly useful as lead compounds for drug development. We have designed and developed a series of substituted pyrroles that inhibit growth and promote death of breast tumor cells at nM and μM concentrations in human breast tumor cell lines. In another project, stilbene analogs were designed and developed as microtubule depolymerizing agents that showed anti-leukemic activity. A molecular modeling study was carried out to accurately represent the complex structure and the binding mode of a new class of tubulin inhibitors that bind at the αβ-tubulin colchicine site. These studies coupled with HINT interaction analyses were able to describe the complex structure and the binding modes of inhibitors. Qualitative analyses of the results showed general agreement with the experimental in vitro biological activity for these derivatives. Consequently, we have been designing new analogs that can be synthesized and tested; we believe that these molecules will be highly selective against cancer cells with minimal toxicity to the host tissue. Another goal of our research is to develop computational tools for drug design. The development and implementation of a novel cavity detection algorithm is also reported and discussed. The algorithm named VICE (Vectorial Identification of Cavity Extents) utilizes HINT toolkit functions to identify and delineate a binding pocket in a protein. The program is based on geometric criteria and applies simple integer grid maps to delineate binding sites. The algorithm was extensively tested on a diverse set of proteins and detects binding pockets of different shapes and sizes. The study also implemented the computational titration algorithm to understand the complexity of ligand binding and protonation state in the active site of HIV-1 protease. The Computational titration algorithm is a powerful tool for understanding ligand binding in a complex biochemical environment and allows generating hypothesis on the best model for binding.

Water soluble platinum complexes are a recent area of emphasis of cisplatin chemistry. The water soluble complexes could have a reduced toxicity compared with cisplatin. Oxaliplatin, which has an oxalate leaving group, has previously been shown to have less nephro-toxicity and higher water solubility than cisplatin. [Pt(en)(oxalate)] (en = ethylenediamine) has been prepared from Pt(en)Cl2 and silver oxalate. This complex has been reacted with methionine and N-acetylmethionine at different molar ratios. At high Pt: methionine ratios, chelates with the sulfur and nitrogen atoms of the methionine are dominant; at lower Pt: methionine ratios, a bis-methionine product is formed. The en ligand is displaced by methionine but not N-acetylmethionine.

Η εργασία εστιάζει στην παρασκευή και μελέτη πολυλειτουργικών μαγνητικών νανοσωματιδίων Ιξαμπεπιλόνης, με σκοπό την χορήγησή τους για την αντιμετώπιση του καρκίνου του μαστού. Πραγματοποιήθηκαν φυσικοχημικές μελέτες, μελέτες αποδέσμευσης και κυτταρικές μελέτες. / The aim of the current study is the preparation and the characterization of multifunctional magnetic Ixabepilone nanoparticles, in order to determine their use for the treatment of advanced breast cancer. Physicochemical studies, release studies and cell studies were performed.