10. GALLIUM COMPLEXES AS ANTICANCER DRUGS
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Christopher R. Chitambar
Abstract
Clinical trials have shown gallium nitrate, a group 13 (formerly IIIa) metal salt, to have antineoplastic activity against non-Hodgkin’s lymphoma and urothelial cancers. Interest in gallium as a metal with anticancer properties emerged when it was discovered that 67Ga(III) citrate injected in tumor-bearing animals localized to sites of tumor. Animal studies showed non-radioactive gallium nitrate to inhibit the growth of implanted solid tumors. Following further evaluation of its efficacy and toxicity in animals, gallium nitrate, Ga(NO3)3, was designated an investigational drug by the National Cancer Institute (USA) and advanced to Phase 1 and 2 clinical trials. Gallium(III) shares certain chemical characteristics with iron(III) which enable it to interact with iron-binding proteins and disrupt iron-dependent tumor cell growth. Gallium’s mechanisms of action include the inhibition of cellular iron uptake and disruption of intracellular iron homeostasis, these effects result in inhibition of ribonucleotide reductase and mitochondrial function, and changes in the expression in proteins of iron transport and storage. Whereas the growth-inhibitory effects of gallium become apparent after 24 to 48 hours of incubation of cells, an increase in intracellular reactive oxygen species (ROS) is seen with 1 to 4 hours of incubation. Gallium-induced ROS consequently triggers the upregulation of metallothionein and hemoxygenase-1 genes. Beyond the first generation of gallium salts such as gallium nitrate and gallium chloride, a new generation of gallium-ligand complexes such as tris(8-quinolinolato)gallium(III) (KP46) and gallium maltolate has emerged. These agents are being evaluated in the clinic while other ligands for gallium are in preclinical development. These newer agents appear to possess greater antitumor efficacy and a broader spectrum of antineoplastic activity than the earlier generation of gallium compounds.
Abstract
Clinical trials have shown gallium nitrate, a group 13 (formerly IIIa) metal salt, to have antineoplastic activity against non-Hodgkin’s lymphoma and urothelial cancers. Interest in gallium as a metal with anticancer properties emerged when it was discovered that 67Ga(III) citrate injected in tumor-bearing animals localized to sites of tumor. Animal studies showed non-radioactive gallium nitrate to inhibit the growth of implanted solid tumors. Following further evaluation of its efficacy and toxicity in animals, gallium nitrate, Ga(NO3)3, was designated an investigational drug by the National Cancer Institute (USA) and advanced to Phase 1 and 2 clinical trials. Gallium(III) shares certain chemical characteristics with iron(III) which enable it to interact with iron-binding proteins and disrupt iron-dependent tumor cell growth. Gallium’s mechanisms of action include the inhibition of cellular iron uptake and disruption of intracellular iron homeostasis, these effects result in inhibition of ribonucleotide reductase and mitochondrial function, and changes in the expression in proteins of iron transport and storage. Whereas the growth-inhibitory effects of gallium become apparent after 24 to 48 hours of incubation of cells, an increase in intracellular reactive oxygen species (ROS) is seen with 1 to 4 hours of incubation. Gallium-induced ROS consequently triggers the upregulation of metallothionein and hemoxygenase-1 genes. Beyond the first generation of gallium salts such as gallium nitrate and gallium chloride, a new generation of gallium-ligand complexes such as tris(8-quinolinolato)gallium(III) (KP46) and gallium maltolate has emerged. These agents are being evaluated in the clinic while other ligands for gallium are in preclinical development. These newer agents appear to possess greater antitumor efficacy and a broader spectrum of antineoplastic activity than the earlier generation of gallium compounds.
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
