Florey Department of Neuroscience and Mental Health - Research Publications

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5-fluorouracil steady state pharmacokinetics and outcome in patients receiving protracted venous infusion for advanced colorectal cancer

Jodrell, DI ; Stewart, M ; Aird, R ; Knowles, G ; Bowman, A ; Wall, L ; Cummings, J ; McLean, C (NATURE PUBLISHING GROUP, 2001-03-02)

PVI 5FU gives increased response rates and reduced toxicity when compared to bolus 5FU (J Clin Oncol 1989, 425-432). PVI 5FU administration was reported to give highly variable (>1000-fold) plasma 5FU concentrations at steady state (FU Css) which correlated with toxicity (Ann Oncol 1996, 47-53); but only 19 patients were studied. Therefore, we performed a study of PVI 5FU in 61 patients with advanced colorectal cancer to assess the variability (inter- and intra-subject) in 5FU Css associated with PVI 5FU (300 mg m(-2)day(-1)) and to attempt to correlate pharmacodynamic end-points (anti-tumour activity, toxicity) with 5FU Css as a prelude to 'exposure-guided' 5FU administration. All 5FU sampling was performed between 10 am and noon. PVI 5FU administration continued to 26 weeks in patients with disease improvement or stabilization. The response rate was 26% (33% stable disease) and median survival was 11 months. Hand-foot syndrome was the most common dose limiting toxicity. Variability in 5FU(300)Css was considerably less than previously reported; 94 +/- 25 ng ml(-1)(CV = 27%). No relationships were demonstrated between subject mean 5FU(300)Css and PD end-points such as response, mucositis, diarrhoea and hand-foot syndrome. The lack of correlation suggests that measurement of 5FU concentrations should not be used to individualize dosing in patients receiving PVI 5FU for advanced colorectal cancer.
Modulation of the equilibrative nucleoside transporter by inhibitors of DNA synthesis.

Pressacco, J ; Wiley, JS ; Jamieson, GP ; Erlichman, C ; Hedley, DW (Springer Science and Business Media LLC, 1995-10)

Expression of the equilibrative, S-(p-nitrobenzyl)-6-thioinosine (NBMPR)-sensitive nucleoside transporter (es), a component of the nucleoside salvage pathway, was measured during unperturbed growth and following exposure to various antimetabolites at growth-inhibitory concentrations. The probe 5-(SAENTA-x8)-fluorescein is a highly modified form of adenosine incorporating a fluorescein molecule. It binds. with high affinity and specificity to the (es) nucleoside transporter at a 1:1 stoichiometry, allowing reliable estimates of es expression by flow cytometry. Using a dual labelling technique which combined the vital DNA dye Hoechst-33342 and 5-(SAENTA-x8)-fluorescein, we found that surface expression of es approximately doubled between G1 and G2 + M phases of the cell cycle. To address the question of whether es expression could be modulated in cells exposed to drugs which inhibit de novo synthesis of nucleotides, cells were exposed to antimetabolite drugs having different modes of action. Hydroxyurea and 5-fluorouracil (5-FU), which inhibit the de novo synthesis of DNA precursors, produced increases in the expression of es. In contrast, cytosine arabinoside (ara-C) and aphidicolin, which directly inhibit DNA synthesis, produced no significant increase in es expression. Thymidine (TdR), which is an allosteric inhibitor of ribonucleotide reductase that depletes dATP, dCTP and dGTP pools while repleting the dTTP pool, had no significant effect on es expression. These data suggest that surface expression of the es nucleoside transporter is regulated by a mechanism which is sensitive to the supply of deoxynucleotides. Because 5-FU (which specifically depletes dTTP pools) causes a large increase in expression whereas TdR (which depletes all precursors except dTTP) does not, this mechanism might be particularly sensitive to dTTP pools.
Metals and Alzheimer's disease

Adlard, PA ; Bush, AI (IOS PRESS, 2006-11-01)

There is increasing evidence to support a role for both the amyloid beta-protein precursor (AbetaPP) and its proteolytic fragment, amyloid beta (Abeta), in metal ion homeostasis. Furthermore, metal ions such as zinc and copper can interact with both AbetaPP and Abeta to potentiate Alzheimer's disease by participating in the aggregation of these normal cellular proteins and in the generation of reactive oxygen species. In addition, metal ions may interact on several other AD-related pathways, including those involved in neurofibrillary tangle formation, secretase cleavage of AbetaPP and proteolytic degradation of Abeta. As such, a dysregulation of metal ion homeostasis, as occurs with both aging and in AD, may foster an environment that can both precipitate and accelerate degenerative conditions such as AD. This offers a broad biochemical front for novel therapeutic interventions.
A beta aggregation and possible implications in Alzheimer's disease pathogenesis

Bharadwaj, PR ; Dubey, AK ; Masters, CL ; Martins, RN ; Macreadie, IG (WILEY, 2009-03-01)

Amyloid beta protein (Abeta) has been associated with Alzheimer's disease (AD) because it is a major component of the extracellular plaque found in AD brains. Increased Abeta levels correlate with the cognitive decline observed in AD. Sporadic AD cases are thought to be chiefly associated with lack of Abeta clearance from the brain, unlike familial AD which shows increased Abeta production. Abeta aggregation leading to deposition is an essential event in AD. However, the factors involved in Abeta aggregation and accumulation in sporadic AD have not been completely characterized. This review summarizes studies that have examined the factors that affect Abeta aggregation and toxicity. By necessity these are studies that are performed with recombinant-derived or chemically synthesized Abeta. The studies therefore are not done in animals but in cell culture, which includes neuronal cells, other mammalian cells and, in some cases, non-mammalian cells that also appear susceptible to Abeta toxicity. An understanding of Abeta oligomerization may lead to better strategies to prevent AD.
Copper binding to the Alzheimer's disease amyloid precursor protein

Kong, GK-W ; Miles, LA ; Crespi, GAN ; Morton, CJ ; Ng, HL ; Barnham, KJ ; McKinstry, WJ ; Cappai, R ; Parker, MW (SPRINGER, 2008-03-01)

Alzheimer's disease is the fourth biggest killer in developed countries. Amyloid precursor protein (APP) plays a central role in the development of the disease, through the generation of a peptide called A beta by proteolysis of the precursor protein. APP can function as a metalloprotein and modulate copper transport via its extracellular copper binding domain (CuBD). Copper binding to this domain has been shown to reduce A beta levels and hence a molecular understanding of the interaction between metal and protein could lead to the development of novel therapeutics to treat the disease. We have recently determined the three-dimensional structures of apo and copper bound forms of CuBD. The structures provide a mechanism by which CuBD could readily transfer copper ions to other proteins. Importantly, the lack of significant conformational changes to CuBD on copper binding suggests a model in which copper binding affects the dimerisation state of APP leading to reduction in A beta production. We thus predict that disruption of APP dimers may be a novel therapeutic approach to treat Alzheimer's disease.
Family clustering of viliuisk encephalomyelitis in traditional and new geographic regions

Vladimirtsev, VA ; Nikitina, RS ; Renwick, N ; Ivanova, AA ; Danilova, AP ; Platonov, FA ; Krivoshapkin, VG ; McLean, CA ; Masters, CL ; Gajdusek, C ; Goldfarb, LG (CENTER DISEASE CONTROL, 2007-09-01)

Viliuisk encephalomyelitis is an acute, often fatal, meningoencephalitis that tends to develop into a prolonged chronically progressive panencephalitis. Clinical, neuropathologic, and epidemiologic data argue for an infectious cause, although multiple attempts at pathogen isolation have been unsuccessful. To assess mechanisms of disease transmission and spread, we studied 6 multiplex families. Secondary cases occurred among genetically related and unrelated persons in a setting of prolonged intrahousehold contact with a patient manifesting the disease. Transmission to unrelated persons was documented in a densely populated region around the city of Yakutsk in which Viliuisk encephalomyelitis had not been previously known. Initially identified in a small Yakut-Evenk population on the Viliui River of eastern Siberia, the disease subsequently spread through human contacts to new geographic areas, thus characterizing Viliuisk encephalomyelitis as an emerging infectious disease.
An Ancient Duplication of Exon 5 in the Snap25 Gene Is Required for Complex Neuronal Development/Function

Johansson, JU ; Ericsson, J ; Janson, J ; Beraki, S ; Stanic, D ; Mandic, SA ; Wikstrom, MA ; Hokfelt, T ; Ogren, SO ; Rozell, B ; Berggren, P-O ; Bark, C ; Frankel, WN (PUBLIC LIBRARY SCIENCE, 2008-11-01)

Alternative splicing is an evolutionary innovation to create functionally diverse proteins from a limited number of genes. SNAP-25 plays a central role in neuroexocytosis by bridging synaptic vesicles to the plasma membrane during regulated exocytosis. The SNAP-25 polypeptide is encoded by a single copy gene, but in higher vertebrates a duplication of exon 5 has resulted in two mutually exclusive splice variants, SNAP-25a and SNAP-25b. To address a potential physiological difference between the two SNAP-25 proteins, we generated gene targeted SNAP-25b deficient mouse mutants by replacing the SNAP-25b specific exon with a second SNAP-25a equivalent. Elimination of SNAP-25b expression resulted in developmental defects, spontaneous seizures, and impaired short-term synaptic plasticity. In adult mutants, morphological changes in hippocampus and drastically altered neuropeptide expression were accompanied by severe impairment of spatial learning. We conclude that the ancient exon duplication in the Snap25 gene provides additional SNAP-25-function required for complex neuronal processes in higher eukaryotes.
An investigation of polymorphisms in the 17q11.2-12 CC chemokine gene cluster for association with multiple sclerosis in Australians

Bugeja, MJ ; Booth, D ; Bennetts, B ; Heard, R ; Rubio, J ; Stewart, G (BMC, 2006-07-26)

BACKGROUND: Multiple sclerosis (MS) is a disorder of the central nervous system (CNS) characterised by inflammation and neuronal degeneration. It is believed to result from the complex interaction of a number of genes, each with modest effect. Chemokines are vital to the migration of cells to sites of inflammation, including the CNS, and many are implicated in MS pathogenesis. Most of the CC chemokine genes are encoded in a cluster on chromosome 17q11.2-12, which has been identified in a number of genome wide screens as being potentially associated with MS. METHODS: We conducted a two-stage analysis to investigate the chemokine gene cluster for association with MS. After sequencing the chemokine genes in several DNA pools to identify common polymorphisms, 12 candidate single-nucleotide polymorphisms (SNPs) were genotyped in a cohort of Australian MS trio families. RESULTS: Marginally significant (uncorrected) transmission distortion was identified for four of the SNPs after stratification for several factors. We also identified marginally significant (uncorrected) transmission distortion for haplotypes encompassing the CCL2 and CCL11 genes, using two independent cohorts, which was consistent with recent reports from another group. CONCLUSION: Our results implicate several chemokines as possibly being associated with MS susceptibility, and given that chemokines and their receptors are suitable targets for therapeutic agents, further investigation is warranted in this region.
STRUCTURAL REQUIREMENTS FOR CHARGED LIPID MOLECULES TO DIRECTLY INCREASE OR SUPPRESS K+ CHANNEL ACTIVITY IN SMOOTH-MUSCLE CELLS - EFFECTS OF FATTY-ACIDS, LYSOPHOSPHATIDATE, ACYL COENZYME-A AND SPHINGOSINE

PETROU, S ; ORDWAY, RW ; HAMILTON, JA ; WALSH, JV ; SINGER, JJ (ROCKEFELLER UNIV PRESS, 1994-03-01)

We determined the structural features necessary for fatty acids to exert their action on K+ channels of gastric smooth muscle cells. Examination of the effects of a variety of synthetic and naturally occurring lipid compounds on K+ channel activity in cell-attached and excised membrane patches revealed that negatively charged analogs of medium to long chain fatty acids (but not short chain analogs) as well as certain other negatively charged lipids activate the channels. In contrast, positively charged, medium to long chain analogs suppress activity, and neutral analogs are without effect. The key requirements for effective compounds seem to be a sufficiently hydrophobic domain and the presence of a charged group. Furthermore, those negatively charged compounds unable to "flip" across the bilayer are effective only when applied at the cytosolic surface of the membrane, suggesting that the site of fatty acid action is also located there. Finally, because some of the effective compounds, for example, the fatty acids themselves, lysophosphatidate, acyl Coenzyme A, and sphingosine, are naturally occurring substances and can be liberated by agonist-activated or metabolic enzymes, they may act as second messengers targeting ion channels.
The neuropathology of kuru and variant Creutzfeldt-Jakob disease

McLean, CA (ROYAL SOC, 2008-11-27)

A comparison of the pathological profiles of two spongiform encephalopathies with a similar presumptive route of infection was performed. Archival kuru and recent variant Creutzfeldt-Jakob disease (vCJD) cases reveal distinct lesional differences, particularly with respect to prion protein, suggesting that the strain of agent is important in determining the phenotype. Genotype analysis of the polymorphism on codon 129 reveals (in conjunction with updated information from more kuru cases) that all three genotypes (VV, MV and MM (where M is methionine and V is valine)) are detected in kuru with some preference for MM homozygosity. The presence of valine does not therefore appear to determine peripheral selection of PrPCJD. vCJD remains restricted to date to MM homozygosity on codon 129. It remains to be determined whether this genotype is dictating a shorter incubation period.