Platinum and Other Metal Coordination Compounds in Cancer Chemotherapy

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.

Synthetic Chemistry and Biochemistry.- Platinum DNA Chemistry.- New Insights About the Interaction of Cisplatinum with Intracellular Components.- Modelling Platinum - DNA Interactions.- From the Modelization of DNA Platination to the Conception of New Drugs.- cis-Diammineplatinum (II) Complexes Tethered to DNA-Affinic Ligands: Antitumor Activity and DNA-binding Properties.- Complexes of Peptides and Related Molecules with Diammineplatinum (II) as Models for Platinum-Protein Interactions.- Reactivity of DNA and cis-Diamminedichloroplatinum (II) in the Presence of Intercalating Agents.- Structurally Novel Platinum Antitumor Compounds.- Synthesis and Reactions of a New Class of Orally Active Platinum (IV) Antitumor Complexes.- Pt-DNA Interactions: Oligonucleotide Models.- New Approaches to the Design of Platinum Antitumor Agents.- Developmental Approach to Prepare New Types of Antitumor Platinum Complexes with Dual Function.- Synthesis and Antitumor Activity of Some Novel Platinum(II) Organoamides and Organometallics.- Biochemical and Molecular Pharmacology.- Role of Membrane Ion Transport in Cisplatin Accumulation.- Enhancement of the Antiproliferative Effect of cis-Diamminedichloroplatinum (II) and Other Antitumor Agents by Inhibitors of Enzymes Involved in Growth Factor Signal-Transduction.- Signal Transduction Pathway Regulation of DDP Sensitivity.- The Role of Platinum-DNA Lesions in the Inhibition of DNA Replication.- Activation of a Genetic Program for Cell Death.- Molecular Aspects of Repair and Mutagenesis of cis-Platin-Induced Lesions.- Isolation of a Gene Associated with Resistance to Cisplatin.- Repair of Damaged DNA In Vitro by Extracts from Human Cell Lines.- Gene Specific Damage and Repair of Platinum Adducts and Crosslinks.- A Protein from Mammalian CellsThat Recognizes Piatinated DNA.- Sensitization of Resistant Human Tumor Cells to Cisplatin or Carboplatin by Inhibitors of DNA Excision Repair.- Carrier Ligand Effects in Platinum-resistant Cell Lines.- Immunocytochemical Analysis of Platinum-DNA Adducts.- Strategies for Increasing the Efficacy of and Overcoming Resistance to Platinum Complexes In Vivo.- The Role of c-fos Oncogenes in Cisplatin Resistance.- Metallothioneins and Cisplatin Resistance.- A New Membrane Protein Associated with Resistance to cis-Platinum and Methotrexate.- Toxicology and Clinical Pharmacology of New Drugs.- Pharmacokinetics of Carboplatin in Children and the Development of a Paediatric Dose Equation.- Clinical Studies with Cisplatin Analogues, 254-S, DWA2114R and NK121.- Clinical and Pharmacokinetic Studies on the New Platinum Complex, Zeniplatin (CL286, 558).- Oxalatoplatinum (I-OHP): Experimental and Clinical Studies.- Pharmacologic Studies with New Liposome-Entrapped Cisplatin Derivatives.- Ammine/Amine Platinum IV Dicarboxylates: A Novel Class of Complexes Which Circumvent Intrinsic Cisplatin Resistance.- Clinical Trials.- Dose Intensity Analysis May Help Resolve Issues in Chemotherapy with Platinum Compounds.- Cisplatin Dose-intensity in Testicular Cancer Treatment: Analysis of a Randomized Clinical Trial.- Phase I/II Study to Further Escalate the Dose of Carboplatin in Combination with GM-CSF in the Treatment of Refractory Ovarian Cancer.- High Dose Carboplatin with Peripheral Blood Stem Cell and Growth Factor Support.- Pharmacologic, Pre-clinical and Clinical Investigations of the Cisplatin/Taxol Combination.- Phase I Trials with Ormaplatin (Tetraplatin).- Intraperitoneal Cisplatin and Carboplatin in the Management of Ovarian Cancer.- Radiotherapy Combined with Daily or Weekly cis-Diamminedichloroplatinum (II) in Inoperable Non-metastasized Non-small Cell Lung Cancer: A Toxicity Report of the Randomized Phase III Study of the EORTC Lung Cancer Cooperative and Radiotherapy Cooperative Groups.- Optimizing Dose-Intensity: Combining Carboplatin with Cisplatin.- High Dose Cisplatin: Modulation of Toxicity.- Probenecid and Diethyldithiocarbamate as Modifiers of Cisplatin Toxicity.- ORG 2766 in the Prevention of Cisplatin Neuropathy.- WR-2721 (Ethyol): Reduction in Toxicity of Anticancer Therapy without Loss of Efficacy.- High-Dose Cisplatin with Glutathione Protection in Gynecologic Malignancies.- Improved Efficacy of "Two-route Chemotherapy" Using Cisplatin and its Antidote, Sodium Thiosulfate in Combination with Angiotensin II.