Platinum and Other Heavy Metal Compounds in Cancer Chemotherapy: Molecular Mechanisms and Clinical Applications (Cancer Drug Discovery and Development)

The platinum-containing chemotherapeutic agents remain key components of many of the most effective regimens for the treatment of cancer. New information about the chemistry, pharmacology and molecular mechanisms by which these drugs work is leading to both the development of new drugs and more effective use of existing members of this class. Better definition of the genetic basis of malignancies is offering intriguing new insights in to how to use these drugs in a more individualized manner. "__Platinum and Other Heavy Metal Compounds in Cancer Chemotherapy: Molecular Mechanisms and Clinical Applications__", edited by Andrea Bonetti, Steve B. Howell, Roberto Leone, and Franco Muggia, provides succinct summaries of the major new developments in field of platinum drug therapy drawn from presentations made at the 10^th^ International Symposium on Platinum Coordination Compounds in Cancer Chemotherapy that took place in Verona, Italy, in December 2007. This meeting, held once every 4 years, brought together the world’s leading investigators working on platinum drugs and their contributions provide a detailed survey of the major research directions in this rapidly evolving field. Front Matter....Pages i-xxvi Platinum Compounds: The Culmination of the Era of Cancer Chemotherapy....Pages 1-7 Studies on New Platinum Compounds....Pages 11-17 Assessment of the In Vivo Antiproliferative Activity of a Novel Platinum Particulate Pharmacophore....Pages 19-25 Nanocapsules of Platinum-Based Anticancer Drugs....Pages 27-32 The Design and Development of the Tumor-Targeting Nanopolymer Dach Platinum Conjugate AP5346 (Prolindac TM )....Pages 33-39 In vitro Anti-proliferative Effects of ProLindacTM, a Novel Dach-Platinum-Linked Polymer Compound, as a Single Agent and in Combination with Other Anti-cancer Drugs....Pages 41-47 Synthesis of Cisplatin Analogues: Cytotoxic Efficacy and Anti-tumour Activity of Bis-Amidine and Bis-Iminoether Pt(II) Complexes....Pages 49-56 Ruthenium Drugs for Cancer Chemotherapy: An Ongoing Challenge to Treat Solid Tumours....Pages 57-66 X-ray Crystal Structure of a Monofunctional Platinum–DNA Adduct, cis -{Pt(NH 3 ) 2 -(Pyridine)} 2+ Bound to Deoxyguanosine in a Dodecamer Duplex....Pages 67-72 Osmium Arenes: A New Class of Potential Anti-cancer Agents....Pages 73-79 Resistance to Cisplatin Results from Multiple Mechanisms in Cancer Cells....Pages 83-88 CTR1 as a Determinant of Platinum Drug Transport....Pages 89-94 Regulation of the Export of Platinum-Containing Drugs by the Copper Efflux Transporters ATP7A and ATP7B....Pages 95-99 Altered Localization of Transport Proteins Associated with Cisplatin Resistance....Pages 101-107 How to Overcome Cisplatin Resistance Through Proton Pump Inhibitors....Pages 109-114 Cellular Resistance to Oxaliplatin and Drug Accumulation Defects....Pages 115-124 Possible Incorporation of Free N7 -Platinated Guanines in DNA by DNA Polymerases, Relevance for the Cisplatin Mechanism of Action....Pages 125-132 Structural and Mechanistic Studies of Anticancer Platinum Drugs: Uptake, Activation, and the Cellular Response to DNA Binding....Pages 135-147 Platinum Drugs and DNA Repair: Lessons from the NCI Panel and Clinical Correlates....Pages 149-155 Differences in Conformation and Conformational Dynamics Between Cisplatin and Oxaliplatin DNA Adducts....Pages 157-169 Regrowth Resistance: Low-Level Platinum Resistance Mediated by Rapid Recovery from Platinum-Induced Cell-Cycle Arrest....Pages 171-176 Targeting Nucleotide Excision Repair as a Mechanism to Increase Cisplatin Efficacy....Pages 177-187 CHK2 and ERCC1 in the DNA Adduct Repair Pathway that Mediates Acquired Cisplatin Resistance....Pages 189-194 Modulation of Survival Pathways in Ovarian Carcinoma Cells Resistant to Platinum Compounds....Pages 195-200 Paraptotic Cell Death Induced by the Thioxotriazole Copper Complex A0: A New Tool to Kill Apoptosis-Resistant Cancer Cells....Pages 201-207 Platinum Compounds and Radiation....Pages 211-223 Treating Cisplatin-Resistant Cancer: A Systematic Analysis of Oxaliplatin or Paclitaxel Salvage Chemotherapy....Pages 225-230 Platinum Compounds in Lung Cancer: Current Status....Pages 231-242 Is Lipoplatinum Monotherapy an Active Alternative in Second Line Treatment of Metastatic Non–Small Cell Lung Cancer? A Phase II Trial....Pages 243-249 Combining Platinums in Gastric Cancer....Pages 251-270 Oxaliplatin-Based Chemotherapy for Colon Cancer....Pages 271-284 First-Line Systemic Chemotherapy with Folfoxiri Followed by Radical Surgical Resection of Metastases for the Treatment of Unresectable Metastatic Colorectal Cancer Patients....Pages 285-293 Pre-operative Radio-Chemotherapy of Rectal Cancer: Toxicity and Preliminary Results with the Addition of Weekly Oxaliplatin....Pages 295-306 The Role of Platins in Newly Diagnosed Endometrial Cancer....Pages 307-315 Platinum Compounds: Key Ingredients in Ovarian Cancer Treatment and Strategies....Pages 317-328 Intraperitoneal Chemotherapy: An Important Strategy in Ovarian Cancer Treatment....Pages 329-333 Novel Strategies for Enhancing the Efficacy of Intraperitoneal Chemotherapy for Patients with Ovarian Cancer....Pages 335-341 Laparoscopically Assisted Heated Intra-Operative Intraperitoneal Chemotherapy (HIPEC): Technical Aspect and Pharmacokinetics Data....Pages 343-351 Organic Cation Transporters 2 as Mediators of Cisplatin Nephrotoxicity....Pages 353-358 Peripheral Neurotoxicity of Platinum Compounds....Pages 359-364 Platinum Drugs in Children with Cancer....Pages 365-371 Optimising Carboplatin Dose using Patient Characteristics and Therapeutic Drug Monitoring....Pages 373-380 Back Matter....Pages 379-383 Cisplatin, the first member of the family of platinum-containing chemotherapeutic agents, was discovered by Barnett Rosenberg in 1965 and approved by the FDA for marketing in 1978. After 30 years of use in the clinic, cisplatin remains a central element of many treatment regimens. Cisplatin is still an irreplaceable component of a regimen that produces high cure rates in even advanced nonseminomatous germ-cell cancers, and is widely used in the treatment of ovarian cancers and other gynecologic cancers, head and neck, and numerous other tumor types. The development of carboplatin has reduced some of the adverse events associated with cisplatin treatment, and the introduction of the DACH platinum compound oxaliplatin has broadened the spectrum of activity of the platinums to include gastro-intestinal cancers, especially colorectal cancer. The clinical importance of this family of drugs continues to drive investigation into how these drugs work and how to improve their efficacy and reduce their toxicity. The papers in this volume were presented in Verona, Italy, during the tenth International Symposium on Platinum Coordination Compounds in Cancer Chemotherapy. The symposium was jointly organized by the Department of Oncology of the Mater Salutis Hospital – Azienda Sanitaria Locale 21 of the Veneto Region – and by the Department of Medicine and Public Health, Section of Pharmacology, the University of Verona. They reflect the vitality of this field and the increasing use of new molecular and cell biologic, genetic, and biochemical tools to identify approaches to further improve their use. The platinum-containing chemotherapeutic agents remain key components of many of the most effective regimens for the treatment of cancer. New information about the chemistry, pharmacology and molecular mechanisms by which these drugs work is leading to both the development of new drugs and more effective use of existing members of this class. Better definition of the genetic basis of malignancies is offering intriguing new insights in to how to use these drugs in a more individualized manner. " Platinum and Other Heavy Metal Compounds in Cancer Chemotherapy: Molecular Mechanisms and Clinical Applications ", edited by Andrea Bonetti, Steve B. Howell, Roberto Leone, and Franco Muggia, provides succinct summaries of the major new developments in field of platinum drug therapy drawn from presentations made at the 10 th International Symposium on Platinum Coordination Compounds in Cancer Chemotherapy that took place in Verona, Italy, in December 2007. This meeting, held once every 4 years, brought together the world’s leading investigators working on platinum drugs and their contributions provide a detailed survey of the major research directions in this rapidly evolving field. Covers the issues related to platinum drugs including the mechanisms of action and resistance; the development of novel platinum compounds and other metal coordination compounds; and, the combination of platinum drugs with targeted therapies for the treatment of common malignancies such as breast, colorectal, lung and gynaecologic cancers