Sydney Cancer Institute University of Sydney 19th Jan 2004
Organisation and Research Direction • The Sydney Cancer Institute is an independent research institute established in February 2003 by: • Sydney Cancer Centre • The Central Sydney Area Heath Service (CSAHS) • The University of Sydney • The Sydney National Cancer Foundation • The primary function of the institute is: “Conducting research to substantially improve cancer outcomes”
Objectives and Research Directions • The Sydney Cancer Institute’s research programs are based around a clinically driven set of research priorities • The Sydney Cancer Institute comprises the following divisions • Molecular Oncology • Cancer Biology • Experimental Therapeutics • Cancer Care and Control
Research Goals • The Sydney Cancer Institute aims to pursue research excellence, depth and relevance by: • Integration with clinical cancer medicine by the development of translational research programs • Providing core research facilities such as: • A clinical cancer register • Statistician and information technology • Shared instruments and operators • A tumour bank available to all SCI researchers • Providing more structured national and international connections
Scientific Advisory Board • The SCI scientific advisory board includes researchers with a diverse array of skills and interests • Prof. W McCarthy (Director Melanoma Foundation) • Prof. J Bishop (Director Sydney Cancer Centre) • Prof. B Armstrong (Head School of Public Health, USyd) • Prof. G Halliday (Department of Dermatology, USyd) • Prof. P Lay (Centre for Heavy Metals Research, USyd) • Prof. B Roufogalis (Pro-Dean Pharmaceutical Chemistry, USyd) • Prof. J Simes (Director NHMRC Clinical Trials Centre, USyd) • Prof. J Thompson (Director Sydney Melanoma Unit) • A/Prof. P Buttow (Executive Director, Medical Psychology Unit, USyd) • A/Prof. M Millward (Head Clinical Research, SCI) • Dr S Clarke (Senior Research Fellow, SCI)
Affiliations • The SCI has affiliation agreements with: • The University of Sydney • Central Sydney Area Health Service • The Sydney National Cancer Foundation • The John Wayne Cancer Institute – Los Angeles • The National Institutes of Health (USA) • National Cancer Institute (CTEP, USA) • Cancer Therapeutics Research Group (Singapore) • National Cancer Centre (Singapore) • John Hopkins (Singapore)
Research programs • The SCI has a diverse research program including: • DNA Methylation (Dr Susan Clarke) • Cancer Genetics and Drug Resistance (Dr Quihan Dong, Dr John Young) • Viral Oncology (Professor Y Cossart and Dr Carol Thompson) • Tumour Pathology and Molecular Biology (A/Prof. Soon Lee) • Skin Cancer Biology (Prof. Gary Halliday) • Skin Cancer and Photobiology (Dr Vivienne Reeve) • Cancer Invasion and Metastasis (Dr Guy Lyons) • Heavy Metals Research Program (Prof. Peter Lay) • Clinical Pharmacology (A/Prof. Stephen Clarke) • Pharmaco Oncology (Prof. Basil Roufogalis) • Gene Therapy (A/Prof John Rasko) • Molecular Imaging (A/Prof Michael Fulham) • Clinical Trials (A/Prof. Michael Millwood) • Early Detection and Diagnosis (Dr Scott Menzies)
Biometals Section Centre for Heavy Metals Research School of Chemistry University of Sydney
Biometals Section, CHMR • Associate Professor Robert Armstrong • Dr. Rachel Codd • Dr Carolyn Dillon • Dr. Ron Fenton • Professor Hans Freeman • Professor Trevor Hambley • Associate Professor Margaret Harding • Dr. Hugh Harris • Associate Professor Brendan Kennedy • Professor Peter Lay • Professor Len Lindoy • Associate Professor Tony Masters • Dr. Lou Rendina
Research Areas/Interests • Anti-Cancer Drugs - Boron complexes: boron neutron capture therapy (Rendina) - Co(III) Hypoxic Agents (Hambley) - Copper Complexes (Dillon, Hambley, Harris, Kennedy, Lay) - Metallocenes (Dillon, Harding) - Metal Complexes of Organic Anti-Cancer Drugs (Hambley, Harding) - Metalloporphyrin/Fullerenes (Armstrong, Lay) - Pt(IV) and Pt(II) (Fenton, Hambley) - Ruthenium (Armstrong, Dillon, Lay) • Radiopharmaceuticals - Use of copper-64 in macrocyclic systems for the imaging and therapy of cancer (Lindoy) - Improved 99Tc Generators (Masters)
Research Areas/Interests • Metal-Induced Cancers and Toxicity - Cr- and Ni-induced cancers (Codd, Dillon, Harris, Lay) - As carcinogenesis and toxicity (Dillon, Harris) • Anti-Inflammatory Drugs - Cu, Zn, Ni, Zn complexes as anti-inflammatories (Dillon, Hambley, Kennedy, Lay) • Anti-Diabetics - Cr(III) (Dillon, Harris, Lay) - Vanadium (Codd, Lay)
Research Areas/Interests • Metalloproteins - structure of heme proteins and their roles in the immune system, and heart disease (Armstrong, Lay) • Chelation Therapy and Metabolic Processes - role of transition metal-sialic acid species in metal homeostasis/disease (Codd) - cold-adapted 'super-siderophores' for metal chelation therapies (Codd). • Diagnostics - use of vibrational spectroscopy in the diagnosis of cancer (Armstrong, Lay)
Facilities/Expertise • Structural Biology and Structural Chemistry X-ray, Neutron & Electron Scattering and Diffraction; Synchrotron Techniques; NMR Spectroscopy; See separate presentation on CSBSC • Mass Spectrometry Electrospray (including HPLC front end); GC-MS; Maldi • Vibrational Spectroscopy IR, Raman and Resonance Raman: including tissue mapping • EPR Spectroscopy L, Q and X band, ENDOR, He cryogenics, Whole cell • Cell Biology Cytotoxicity; Genotoxicity; Permeability; Imaging, Spectroscopy • Animal Studies Pharmacology; Pharmacokinetics; Efficacy; Toxicity
4 1 He n kinetic 10 11 B B* 7 Li Boron Neutron Capture - Rendina 2 0 + energy (~2.28 MeV) 5 5 3
Clinical BNCT Agents Malignant brain tumours Malignant melanoma • Two new classes: • Platinum(II)-amine complexes • Metallo-intercalator complexes
Dinuclear Platinum Complexes Woodhouse, S. L.; Rendina, L. M.Chem. Commun., 2001, 2464. International Patent PCT/AU02/00943
Metallo-intercalator Complexes Todd, J. A.; Rendina, L. M. Inorg. Chem., 2002, 41, 3331. International Patent PCT/AU02/00943.
P S Cl K Cr Fe Ni Ca Zn Cu Scattering Control A375 Melanoma Cells J. Aitken, H. Harris, P. A. Lay, USyd, P. Farmer, UC Irvine
P S Cl K Cr Fe Ni Ca Zn Cu Scattering CuDSF-treated A375 Melanoma Cells J. Aitken, H. Harris, P. A. Lay, USyd, P. Farmer, UC Irvine
Cu XANES of Melanoma Cells J. Aitken, H. Harris, P. A. Lay, USyd, P. Farmer, UC Irvine
Pt(IV) Pt(II) Selective activation in solid tumours Hambley necrotic Pt(IV) suboxic normoxic
MicroXANES of Pt obtained from A2780 ovarian cancer cells treated with Pt(IV)
Identification of Novel Intercalating Platinum Compounds - Fenton, Aldrich-Wright CISPLATIN & analogs bind to DNANew Pt compounds intercalate into DNA - IP protection- PCT filing, Priority date February 22nd 2001
EFFICACY of lead compound - Comparison with Cisplatin & in Cisplatin-resistant cell lines L1210 = mouse leukemia; 2008 = human ovarian tumor PC3= prostate tumor DDP = Cisplatin-resistant; C13 = acquired; SKOV3= intrinsic Cisplatin resistance
Titanocene Dichloride Phase I clinical trials • toxic effects : hypoglycaemia, metallic after taste • bone marrow largely unaffected • liver toxicity does-limiting side-effect Phase II clinical trials • breast cancer • renal cell carcinoma • poor hydrolytic stability in water pH> 4.0 • Ti accumulates in nucleic rich regions tumour cells • species formed in vivo and how interaction with DNA occurs not understood • mechanism is distinct from platinum based drugs A/Prof Margaret Harding, School of Chemistry
Antitumour Metallocenes Ti V Mn Cr Zr Tc Nb Mo Hf Ta W Re Y = Cl, Br, I, NCS, N3 • Each complex has independent mechanism of action • Current studies focus on cellular distribution, interaction with biomolecules of Mo, Nb complexes • M = Mo targets thiols Design water soluble, stable derivs A/Prof Margaret Harding, School of Chemistry
Streptonigrin • Clinical use human cancers until 1977 • broad spectrum antitumor activity • lymphoma, melanoma • cancers of the breast, cervix, head, neck • severe and unpredictable side-effects Water, pH 6.5 A/Prof Margaret Harding, School of Chemistry
Streptonigrin Metal Complexes affects DNA binding topo II recognition site Redox related to DNA cleavage ACCELERATED BY METAL IONS bipyridyl labile metal complexes zwitterion • Ru(II) complex • Reductively activated to semiquinone • Strong DNA binding/cleavage predicted A/Prof Margaret Harding, School of Chemistry
Improved Tc-99 Generators - Masters Understanding the interactions between alumina and molybdates has led to improvements in the process for generating 99Tc for radio-diagnostics Schematic outline of 99Mo production process at ANSTO.
? Cellular Metabolism of Chromium
Effect of Oxidation State on Cr Genotoxicity } Cr(VI) } Cr(V) } Cr(III) Dillon, C. T.; et al.Chem. Res. Toxicol.1998, 11, 119-129; Dillon, C. T.; et al.Chem. Res. Toxicol.2000, 13, 742-748.
Exposure of Whole Cells to Cr(VI) and Cr(III) Cr(III)-Treated Cell P K Cr Zn Cr(VI)-Treated Cell P K Cr Zn Min Max Dillon, C. T.; Lay, P. A.; Kennedy, B. J.;Stampfl, A. P. J.; Cai, Z.; Ilinski, P.; Rodrigues, W.; Legnini, D. G.; Lai, B.; Maser, J. J. Biol. Inorg. Chem. 2002, 7, 640-645.
Copper Indomethacin Lay, Hambley, Kennedy, Dillon • Copper indomethacin is a dimeric copper complex containing 4 indomethacin ligands bound to Cu through the carboxylic acid group. • Cu-algesic (CuIndo) is an effective anti-inflammatory drug commonly used in dogs and horses. • Importantly, CuIndo is much less TOXIC in dogs than IndoH.
Copper Indomethacin Indomethacin Assessment of Small Intestinal Ulceration
Effect of the Formulation on Gastro-Intestinal Damage • Equivalent doses of indomethacin (10 mg/kg) were administered to each animal. • The number of animals tested per treatment ranged from 4-6.
Anti-Diabetics Codd, Harris, Lay
Efficacy of Cr Dietary Supplements • Chromium supplements are the second biggest market for dietary supplements (over $1B industry). • Taken to convert fat into muscle in athletes (used instead of steroids for humans) and food animals. • Used to help prevent diabetes. • There is no compelling evidence (epidemiology, cell work, or biochemical assays) that Cr supplements convert fat into muscle or help prevent diabetes. • The FDA has prevented companies from advertising such health benefits. • There are anti-diabetic effects exhibited in animal studies for certain Cr complexes and they are believed to have anti-diabetic effects on humans.
Side-Effects of Cr Dietary Supplements • They react with enzyme systems such as glucose oxidase and xanthine oxidase to form highly genotoxic mixtures of high oxidation state Cr species, which are very damaging to DNA • The Cr(VI) generated in these enzymatic processes and strongly inhibits phosphatase enzymes, which is likely to be responsible for the anti-diabetic effects of Cr supplements • High-oxidation-state Cr and V species appear to act in the same way, through similar intermediates in their anti-diabetic effects Inhibition of PTP (phosphatase enzyme by Cr(VI), Cr(V) and V(V). Mulyani, Levina, Lay, JACS, submitted
Heme Proteins - Armstrong, Harris, Lay • Characterized NO, CO and O2 adducts of heme proteins, many of which are too unstable to crystallise • Studied unfolding of cytochrome c • Collaborations with Paul Witting and Roland Stocker - Studies on indolamine 2,3-dioxygenase (IDO) - important in the immune system - Studies on the roles of heme proteins in heart disease
HemeProteins Rich, Cheng, Armstrong and Lay
Metal-Sialic Acid Speciation Codd Insight into the nature and role of species formed between sialic acid and transition metal ions. This polyfunctional carbohydrate is present as the terminal residue in many glycopoteins involved in metal transport (e.g., transferrin; ceruloplasmin) Membrane glycoproteins and glyco- lipids: extracellular sugar residues on mammalian plasma membranes
Metal-Sialic Speciation •Extension of studies of metal-sialic acid speciation with other biologically relevant transition metal ions (e.g., Cu, Fe, Zn, V). Cu(II)-sialic acid profile Cr(V)-sialic acid profile •Implications for metal transport, homeostasis, and role(s) in sialylglycoprotein-dependent disease •Development of transition metal EPR Spectroscopy as a diagnostic technique for glycosylation patterns
IDC IDC Vibrational Spectroscopy in Breast Cancer Diagnosis - Tam, Armstrong, Carter, Lay