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 Role 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-03-8799 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-active Molecules 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.

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 ...

Interest in the biological effects of ionising radiation closely followed the identification of such radiation. The realisation that DNA is the site of genetic infonnation in cells subsequently focussed attention on DNA as an important target in the lethal and mutagenic effects of ionising radiation. Thus radiation effects upon DNA became an important area for fundamental scientific studies by radiation biologists, chemists and physicists. To a first approximation, the concerns of the three disciplines can be divided by time scales: the physical process of energy deposition from photon or charged 16 12 particle and subsequent relaxation (-10- to 10- secs), followed by chemical 12 2 reactions (- 10- to 10 secs), and fmally, the expression of biological effect (minutes to years). Thus, the concept of 'early processes' conveys different ideas to different scientists, although they are all interrelated. To attempt to describe in any detail all these processes is a mammoth task which is not made easier by the different conventions and experimental approaches of the three disciplines. However, the recent advances in all these scientific areas seemed, to the organisers at least, to offer the opportunity to stimulate more active interaction between physicists, chemists and biologists. With this in mind, a multi-disciplinary workshop was organised, which brought together some fifty scientists to present their own specialist interests and, through extensive discussion, explore which problems are of high priority and require input from the different disciplines to resolve them.