Selective Activation of Drugs by Redox Processes

This Workshop, under the auspices of the NATO Advanced Research Workshop program, was organised to review the current status of research into redox-activated compounds particularly bioreductive drugs, and their applications in various fields of medicine, both as diagnostic and therapeutic agents. The Workshop brought together key workers in this currently expanding field of research, i.e. clinici ans, pharmacologists, biochemists and molecular scientists. The programme consisted of several sections including general review lectures, presentations of laboratory-based and clinical research, some poster presentations and general "round table" discussions. The topics ranged from oxygen effects in biological processes, the nature and function of redox proteins particularly those involved in drug activation, the bioactivation of drugs used as sensitizers in radiation oncology, novel approaches to anti-cancer chemotherapy, anti-bacterial agents, non-steroidal anti-inflammatory drugs, anti-oxidants and varous clinical applications of chemical modifiers. G.E. ADAMS A. BRECCIA E.M. FIELDEN P. WARDMAN v ACKNOWLEDGEMENTS The Organisers gratefully acknowledge the following for their generous financial support: ARW-NATO Comune di Fermo, Italy Cas sa di Risparmio di Fermo Istituto di Scienze Chimiche, Bologna, Italy Pharm. Group ALFA, r,assermann, Schiapparplli, Italy Sadam Indu~tr ie.-' Pharmex Corp., Bologna, Italy vii CONTENTS Characteristics of Hypoxic Cells that Enhance their Susceptibility to Chemical Injury . . . .

Klappentext

Proceedings of a NATO ARW held in Fermo, Italy, August 28-September 1, 1989

Zusammenfassung
Proceedings of a NATO ARW held in Fermo, Italy, August 28-September 1, 1989

Inhalt
Characteristics of Hypoxic Cells that Enhance their Susceptibility to Chemical Injury.- Prediction and Measurement of Redox Properties of Drugs and Biomolecules.- Metal-Catalyzed Redox Processes in Biological Systems and Drug Activation.- Redox Systems Generated by Electro-chemical Oxidations and Reductions.- The Rôle of DNA Damage in the Bioreductive Action of 2-Nitroimidazoles.- Redox Properties of Radiation Induced Free Radicals.- Reduction of Bleomycin-Fe by Reductases and Active Oxygen Formation.- Redox Activation of Drugs by the Red Blood Cell Membrane.- Induction of Stress Proteins and Drug Resistance by Hypoxia and Applications of Magnetic Resonance Spectroscopy and Cryospectrophotometry for Detecting Hypoxia in Tumors.- Mechanisms of Activation of Mitomycin C and AZQ in Aerobic and Hypoxic Mammalian Cells.- Molecular Interactions and Biological Effects of the Products of Reduction of Nitroimidazoles.- Redox Activation of Benzotriazine N-oxides: Mechanisms and Potential as Anticancer Drugs.- Nitroacridines and Nitroquinolines as DNA-affinic Hypoxia-selective Cytotoxins.- Metabolic Effects of Hypoxic Cell Sensitizers.- Does Ro-038799 Concentration in Human Tumour Xenografts Predict Radiosensitization? Comparison with SR-2508.- Enzyme-directed Bioreductive Drug Development.- Improved Treatment of Tumours in vivo by Combining the Bioreductive Drug, RSU-1069, Hydralazine and Hyperthermia.- Assessment of Bioreductive Drug Toxicity in vitro and in Experimental Tumours in vivo.- Activity of Bioreductive Agents in Human and Rodent Tumor Cells.- The Control of Tumour Oxygenation in Mice: The Importance of Tumour Site.- Critical Events in the Toxicity of Redox Active Drugs.- The Reductive Activation of Nitroimidazoles; Modification by Oxygen and other Redox-activeMolecules in Cellular Systems.- Fluorescent Probes for Hypoxia: Chemical Aspects.- Toxicity of Metal Complexes with Radiosensitizing Properties.- Effects on DNA of Bioreducible Nitroimidazole and Benzotriazine Drugs.- Response of Repair and Reduction Deficient Mutants to Agents Requiring Bioreduction.- Bioreductive Drugs and Radiation: Pharmacokinetics and Clinical Trials of Etanidazole Radiosensitizer.- The Oncogenic Potential of Bioreductive Drugs.- Adduct Formation by 2-Nitroimidazole in Mammalian Cells: Optimization of Markers for Tissue Oxygenation.- Tumour Blood Flow and its Modulation: Implications for Bioreductive Drug Activity in vivo.- Poster Presentations.- Participants.