Platinum And Other Heavy Metal Compounds In Cancer Chemotherapy

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.

Taken together the data presented in this review, and work by many other investigators, support the notion that DNA excision repair is important in a tumor cell's resistance to platinum compounds. Inhibition of this repair system by combination chemotherapy with the excision repair inhibitors HU and Ara-C produces synergistic cell kills and increased levels and persistance of DNA interstrand crosslinks. The studies with cis-DDP and ~-DDP in combination with UV induced thymine dimers suggest that there may be competition for DNA repair enzymes between the dimer and the platinum lesion. Whether the competing lesion is an intrastrand crosslink, interstrand crosslink, or platinum monoadduct (or all of these lesions) cannot be determined. The similarity between an intrastrand crosslink and a cyclobutane dimer suggests that these lesions may compete for repair. However, the increased peak levels of interstrand crosslinks, and increased persistence of these lesions at later time points suggest that this lesion may also be a substrate for the repair system. These observations may be of clinical relevance. Recently Dr. Kathy Albain of our institution has completed a Phase III I study using a 12 hour pretreatment with HU and Ara-C in patients prior to their cis-DDP therapy. She observed a significant number of responders in this trial (54). She is currently completing a second Phase IIII study substituting IV HU for the oral formulation. We anticipate initiating other clinical trials based upon these observations.

The 7th International Symposium on Platinum and other metal coordination compounds in Cancer Chemotherapy, ISPCC '95, organized by the European Cancer Centre, was held in Amsterdam, the Netherlands, March 1-4, 1995. As with previous ISPCC meetings, the goal of ISPCC '95 was to bring together c1inicians, clinical investigators, scientists, and laboratory workers from many disciplines to promote further collaboration and cooperation in the development of new platinum and other metal coordination compounds as weil as in new ways to use 'c1assical' drugs as cisplatin and carboplatin in the treatment of cancer. Important aspects addressed by experts in the field inc1uded the synthesis and activity of new platinum compounds, the biochemistry and molecular pharrnacology as weil as the c1inical pharrnacology of this c1ass of antineoplastic agents, an overview of current c1inical studies, one special minisymposium on the mechanisms of cell kill of platinum, and one on resistance against platinum compounds. Finally, the current status of development of nonplatinum metal complexes was discussed. This volume contains the contributions of the various speakers at ISPCC '95 and provides an up-to-date and comprehensive overview of this important c1ass of anticancer agents, ranging from synthesis and molecular pharrnacology on one hand to c1inical pharrnacology and cIinical investigations on the other hand. The Organizing Corrunittee and Editors wish to express their gratitude to the contributors to this volume, to the various organizations and pharrnaceutical companies for their generous sponsoring of ISPCC '95, and to the Plenum Publishing Company for their help in producing this volume.

Proceedings of the Fifth International Symposium, held in Abano Terme (Padova), italy, June 29-July 2, 1987

With contributions by numerous experts

Holland-Frei Cancer Medicine, Ninth Edition, offers a balanced view of the most current knowledge of cancer science and clinical oncology practice. This all-new edition is the consummate reference source for medical oncologists, radiation oncologists, internists, surgical oncologists, and others who treat cancer patients. A translational perspective throughout, integrating cancer biology with cancer management providing an in depth understanding of the disease An emphasis on multidisciplinary, research-driven patient care to improve outcomes and optimal use of all appropriate therapies Cutting-edge coverage of personalized cancer care, including molecular diagnostics and therapeutics Concise, readable, clinically relevant text with algorithms, guidelines and insight into the use of both conventional and novel drugs Includes free access to the Wiley Digital Edition providing search across the book, the full reference list with web links, illustrations and photographs, and post-publication updates

Mark R. Kelley