1. CISPLATIN AND OXALIPLATIN: OUR CURRENT UNDERSTANDING OF THEIR ACTIONS
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Imogen A. Riddell
Abstract
Following the serendipitous discovery of the anticancer activity of cisplatin over 50 years ago, a deep understanding of the chemical and biochemical transformations giving rise to its medicinal properties has developed allowing for improved treatment regimens and rational design of second and third generation drugs. This chapter begins with a brief historical review detailing initial results that led to the worldwide clinical approval of cisplatin and development of the field of metal anticancer agents. Later sections summarize our understanding of key mechanistic features including drug uptake, formation of covalent adducts with DNA, recognition and repair of Pt-DNA adducts, and the DNA damage response, with respect to cisplatin and oxaliplatin. The final section highlights known shortcomings of classical platinum anticancer agents, including problems with toxicity and mutagenicity, and the development of resistance and enrichment of cancer stem cells brought about through treatment. Instances where specific differences in the response or mechanism of action of cisplatin versus oxaliplatin have been demonstrated are discussed in the text. In this manner the chapter provides a broad overview of our current understanding of the mechanism of action of platinum anticancer agents, providing a framework for improving the rational design of better Pt-based anticancer agents.
Abstract
Following the serendipitous discovery of the anticancer activity of cisplatin over 50 years ago, a deep understanding of the chemical and biochemical transformations giving rise to its medicinal properties has developed allowing for improved treatment regimens and rational design of second and third generation drugs. This chapter begins with a brief historical review detailing initial results that led to the worldwide clinical approval of cisplatin and development of the field of metal anticancer agents. Later sections summarize our understanding of key mechanistic features including drug uptake, formation of covalent adducts with DNA, recognition and repair of Pt-DNA adducts, and the DNA damage response, with respect to cisplatin and oxaliplatin. The final section highlights known shortcomings of classical platinum anticancer agents, including problems with toxicity and mutagenicity, and the development of resistance and enrichment of cancer stem cells brought about through treatment. Instances where specific differences in the response or mechanism of action of cisplatin versus oxaliplatin have been demonstrated are discussed in the text. In this manner the chapter provides a broad overview of our current understanding of the mechanism of action of platinum anticancer agents, providing a framework for improving the rational design of better Pt-based anticancer agents.
Kapitel in diesem Buch
- Frontmatter i
- About the Editors v
- Historical Development and Perspectives of the Series vii
- Preface to Volume 18 ix
- Contents xiii
- Contributors to Volume 18 xix
- Titles of Volumes 1–44 in the Metal Ions in Biological Systems Series xxiii
- Contents of Volumes in the Metal Ions in Life Sciences Series xxv
- 1. CISPLATIN AND OXALIPLATIN: OUR CURRENT UNDERSTANDING OF THEIR ACTIONS 1
- 2. POLYNUCLEAR PLATINUM COMPLEXES. STRUCTURAL DIVERSITY AND DNA BINDING 43
- 3. PLATINUM(IV) PRODRUGS 69
- 4. METALLOGLYCOMICS 109
- 5. THE DECEPTIVELY SIMILAR RUTHENIUM(III) DRUG CANDIDATES KP1019 AND NAMI-A HAVE DIFFERENT ACTIONS. WHAT DID WE LEARN IN THE PAST 30 YEARS? 141
- 6. MULTINUCLEAR ORGANOMETALLIC RUTHENIUM-ARENE COMPLEXES FOR CANCER THERAPY 171
- 7. MEDICINAL CHEMISTRY OF GOLD ANTICANCER METALLODRUGS 199
- 8. COORDINATION COMPLEXES OF TITANIUM(IV) FOR ANTICANCER THERAPY 219
- 9. HEALTH BENEFITS OF VANADIUM AND ITS POTENTIAL AS AN ANTICANCER AGENT 251
- 10. GALLIUM COMPLEXES AS ANTICANCER DRUGS 281
- 11. NON-COVALENT METALLO-DRUGS: USING SHAPE TO TARGET DNA AND RNA JUNCTIONS AND OTHER NUCLEIC ACID STRUCTURES 303
- 12. NUCLEIC ACID QUADRUPLEXES AND METALLO-DRUGS 325
- 13. ANTITUMOR METALLODRUGS THAT TARGET PROTEINS 351
- 14. METALLOINTERCALATORS AND METALLOINSERTORS: STRUCTURAL REQUIREMENTS FOR DNA RECOGNITION AND ANTICANCER ACTIVITY 387
- 15. IRON AND ITS ROLE IN CANCER DEFENSE: A DOUBLE-EDGED SWORD 437
- 16. COPPER COMPLEXES IN CANCER THERAPY 469
- 17. TARGETING ZINC(II) SIGNALLING TO PREVENT CANCER 507
- SUBJECT INDEX 531
Kapitel in diesem Buch
- Frontmatter i
- About the Editors v
- Historical Development and Perspectives of the Series vii
- Preface to Volume 18 ix
- Contents xiii
- Contributors to Volume 18 xix
- Titles of Volumes 1–44 in the Metal Ions in Biological Systems Series xxiii
- Contents of Volumes in the Metal Ions in Life Sciences Series xxv
- 1. CISPLATIN AND OXALIPLATIN: OUR CURRENT UNDERSTANDING OF THEIR ACTIONS 1
- 2. POLYNUCLEAR PLATINUM COMPLEXES. STRUCTURAL DIVERSITY AND DNA BINDING 43
- 3. PLATINUM(IV) PRODRUGS 69
- 4. METALLOGLYCOMICS 109
- 5. THE DECEPTIVELY SIMILAR RUTHENIUM(III) DRUG CANDIDATES KP1019 AND NAMI-A HAVE DIFFERENT ACTIONS. WHAT DID WE LEARN IN THE PAST 30 YEARS? 141
- 6. MULTINUCLEAR ORGANOMETALLIC RUTHENIUM-ARENE COMPLEXES FOR CANCER THERAPY 171
- 7. MEDICINAL CHEMISTRY OF GOLD ANTICANCER METALLODRUGS 199
- 8. COORDINATION COMPLEXES OF TITANIUM(IV) FOR ANTICANCER THERAPY 219
- 9. HEALTH BENEFITS OF VANADIUM AND ITS POTENTIAL AS AN ANTICANCER AGENT 251
- 10. GALLIUM COMPLEXES AS ANTICANCER DRUGS 281
- 11. NON-COVALENT METALLO-DRUGS: USING SHAPE TO TARGET DNA AND RNA JUNCTIONS AND OTHER NUCLEIC ACID STRUCTURES 303
- 12. NUCLEIC ACID QUADRUPLEXES AND METALLO-DRUGS 325
- 13. ANTITUMOR METALLODRUGS THAT TARGET PROTEINS 351
- 14. METALLOINTERCALATORS AND METALLOINSERTORS: STRUCTURAL REQUIREMENTS FOR DNA RECOGNITION AND ANTICANCER ACTIVITY 387
- 15. IRON AND ITS ROLE IN CANCER DEFENSE: A DOUBLE-EDGED SWORD 437
- 16. COPPER COMPLEXES IN CANCER THERAPY 469
- 17. TARGETING ZINC(II) SIGNALLING TO PREVENT CANCER 507
- SUBJECT INDEX 531
