[Frontiers in Bioscience 13, 3506-3524, May 1, 2008] 3506 Neurotoxic effects of antineoplastic drugs: the lesson of pre-clinical studies Guido Cavaletti, Gabriella Nicolini, Paola Marmiroli Department of Neurosciences and Biomedical Technologies, University of Milan “Bicocca”, Monza, Italy TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Mechanisms of action of the neurotoxic antineoplastic compounds 3.1. Platinum-derived drugs 3.1.1. Cisplatin 3.1.2. Carboplatin 3.1.3. Oxaliplatin 3.2. Antitubulin agents 3.2.1. Paclitaxel 3.2.2. Docetaxel 3.2.3. Epothilones 3.2.4. Vinka alkaloids 3.3. Proteasome inhibitors 3.4. Thalidomide 4. Clinical aspects of CIPN 5. Pre-clinical studies 5.1. In vitro models 5.2. In vivo models 6. Pathogenesis of CIPN and neuroprotection 6.1. Antioxidants 6.2. Growth factors 6.3. Detoxicants 6.4. Ions and channel modulators 6.5. Other compounds 7. Conclusion 8. Acknowledgments 9. References 1. ABSTRACT Several antineoplastic drugs induce severe toxic damage of the peripheral nervous system and chemotherapy-induced peripheral neurotoxicity (CIPN) can be dose limiting. Moreover, CIPN signs and symptoms can be permanent and severely impair the patients’ quality of life even after drug withdrawal. Despite extensive investigation, the exact mechanisms of neurotoxic action at the basis of CIPN are not completely known and it is likely that they can be at least in part different from the mechanisms of antineoplastic action of the drugs. A possible instrument to investigate on this important issue is represented by the evaluation of the effect of compounds used to reduce the toxicity of antineoplastic drugs in pre- clinical and clinical settings. This review will be focused on the most clinically-relevant neurotoxic antineoplastic drugs and on the results obtained with several different classes of putative neuroprotectants. 2. INTRODUCTION The use of antineoplastic drugs has markedly improved the prognosis of cancer patients. However, an emerging and clinically-relevant problem in the administration of several of these compounds is represented by their side effects (1-7). Given their mechanisms of action, most of the antineoplastic drugs are toxic not only on fast-replicating cancer but also on normal cells; however, a significant proportion of effective agents can also be neurotoxic. In these cases the dorsal root ganglia and the peripheral nerves are the most common sites of damage, since the central nervous system is protected by an effective blood-brain barrier. Despite the well-established clinical and experimental observation that several antineoplastic drugs induce peripheral neurotoxicity, the fine mechanisms of this side effect is unclear, particularly in view of the absence of cell replication in normal adult neurons which should protect them from anti-mitotic drugs.