ABC Transporters and Cancer.

Front Cover -- ABC Transporters and Cancer -- Copyright -- Dedication -- Contents -- Contributors -- Preface -- Chapter 1: Apical ABC Transporters and Cancer Chemotherapeutic Drug Disposition -- 1. Introduction to Apical ABC Transporters -- 2. Impact of Apical ABC Transporters on Intestinal Absorption of Oral Chemotherapeutic Drugs -- 2.1. Apical ABC transporters affecting the oral bioavailability of taxanes -- 2.1.1. ABCB1 and oral taxane availability -- 2.1.2. ABCC2 and oral taxane availability -- 2.1.3. ABCB1 inhibitors to improve taxane oral availability -- 2.1.4. Assessing CNS toxicity risks of using ABCB1 inhibitors to improve oral taxane availability -- 2.1.5. Possible effects of ABCB1 inhibitors on enhancing taxane antitumor efficacy -- 2.2. Apical ABC transporters in the oral bioavailability of rationally designed anticancer drugs -- 2.2.1. Tyrosine kinase inhibitors -- 2.2.2. PARP inhibitors -- 2.2.3. Chemical inhibition of transporters to increase oral availability of rationally designed anticancer drugs -- 2.2.4. Importance of the sensitivity and specificity of in vitro assays used to assess ABC transporter substrates -- 3. Impact of Apical ABC Transporters on Brain Disposition of Oral Chemotherapeutic Drugs -- 3.1. Does the BBB matter in drug delivery to brain tumors? -- 3.2. Apical efflux transporters in the BBB affecting brain accumulation of anticancer drugs -- 3.2.1. Drugs affected mostly by Abcb1a but also by Abcg2 in their brain accumulation -- 3.2.2. Drugs only affected by Abcb1a in their brain accumulation -- 3.2.3. Drugs affected mostly by Abcg2 but also by Abcb1a in their brain accumulation -- 3.2.4. Three different apical BBB ABC efflux transporters affect brain accumulation of some camptothecins -- 3.2.5. Models to explain the disproportionate effect of combined deficiency of Abcb1 and Abcg2 on brain accumulation of s.

3.2.6. Why are many rationally designed anticancer drugs still ABCB1 and/or ABCG2 substrates? -- 3.2.7. Limitations of knockout mouse models to study ABC transporter functions at the BBB -- 3.2.8. Tissue and cellular context may affect the in vivo impact of apical ABC efflux transporters -- 3.2.9. Use of chemical inhibitors to enhance brain accumulation of ABC transporter substrate drugs -- 4. Concluding Remarks -- References -- Chapter 2: Regulation of ABC Transporters Blood-Brain Barrier: The Good, the Bad, and the Ugly -- 1. Introduction -- 2. Blood-Brain Barriers -- 2.1. Assessing blood-brain barrier function -- 3. ABC Transporters at the Blood-Brain Barrier -- 4. The Bad and the Ugly: Mechanisms that Increase Transporter Expression and Reduce Drug Delivery to the CNS -- 4.1. Xenobiotic-activated transcription factors -- 4.2. Stress-activated transcription factors -- 4.3. Disease -- 5. The Good: Mechanisms that Reduce Transporter Activity/Expression and Have the Potential to Improve Drug Delivery to th... -- 5.1. P-glycoprotein -- 5.2. BCRP -- 6. Perspectives: Where the Field Is Headed -- References -- Chapter 3: Molecular Basis of the Polyspecificity of P-Glycoprotein (ABCB1): Recent Biochemical and Structural Studies -- 1. Introduction -- 2. Molecular Basis of Polyspecificity -- 2.1. Structural flexibility revealed by X-ray crystallography -- 2.2. Structural flexibility probed with disulfide cross-linking and biophysical methods -- 2.3. Substrate polyspecificity and ligand-based studies -- 2.4. P-glycoprotein portals -- 2.5. Drug-binding sites -- 2.6. The proposed R, H, and P sites -- 2.7. Primary and secondary sites -- 2.8. Pseudo-symmetric sites -- 3. Molecular Modeling Studies -- 4. Conclusions and Perspectives -- Acknowledgments -- References -- Chapter 4: Lipid Regulation of the ABCB1 and ABCG2 Multidrug Transporters.

1. Introduction-The Complex Interactions of Lipids and ABC Multidrug Transporters -- 2. Effects of Lipids on the Function of ABCB1 and ABCG2 -- 2.1. Localization of ABCB1 and ABCG2 in specialized membrane domains -- 2.2. Substrate handling of ABCB1 and ABCG2 and the role of membrane lipids -- 2.3. Modulation of ABCB1 and ABCG2 function by lipids, lipid derivatives, and detergents -- 2.4. Role of lipids in MDR-ABC protein purification and reconstitution -- 2.5. MDR-ABC transporters may actively alter the membrane lipid environment -- 3. Effects of Lipids on the Expression of ABCB1 and ABCG2: Regulation by Nuclear Receptors -- 3.1. The NR superfamily of transcription factors and lipid-sensing NRs -- 3.2. Regulation of the expression of ABCB1 by NRs -- 3.3. Regulation of the expression of ABCG2 by NRs -- 3.4. Role of NRs in lipid metabolism and a potential indirect effect on ABCB1 and ABCG2 transporter function -- 4. Experimental Strategies to Define the Lipid-Interacting Regions of the ABCB1 and ABCG2 Proteins -- 4.1. Lipid sensing by the ABCB1 protein -- 4.1.1. Mutagenesis studies in ABCB1 -- 4.1.2. Direct binding of lipids and MD simulations on ABCB1 -- 4.2. Lipid sensing by the ABCG2 protein -- 4.2.1. Role of the R482 position -- 4.2.2. Role of the LxxL motif -- 4.2.3. Role of the CRAC motif -- 5. In Silico Modeling of the Lipid Interactions of ABCB1 and ABCG2 -- 5.1. MD simulation -- 5.2. In silico docking -- 6. Conclusions -- References -- Chapter 5: ABC Transporters and Neuroblastoma -- 1. Introduction -- 2. Current Therapies for Neuroblastoma -- 3. MYCN -- 4. MYCN and ABC Transporters -- 4.1. ABCB1 -- 4.2. ABCG2 -- 4.3. ABCC1 -- 4.4. ABCC3 -- 4.5. ABCC4 -- 5. Non-Drug Transport Roles of ABCC1, ABCC3, and ABCC4 in Cancer Biology -- 6. Development of Therapeutic ABCC1 and ABCC4 Inhibitors.

7. Considerations for Targeting ABCC1 and ABCC4 in Cancer -- 8. Conclusions -- References -- Chapter 6: Leukemia and ABC Transporters -- 1. Hematopoiesis and Leukemia -- 1.1. Hematopoietic stem cells and ABC transporters -- 1.2. Leukemic stem cells -- 1.3. AML chemotherapy and ABC transporters -- 2. ABC Transporters That Export Regulatory Molecules -- 2.1. Cyclic nucleotides-cAMP -- 2.2. MRP4 and cAMP -- 2.3. Prostaglandins -- 2.4. Prostaglandin and HSCs -- 2.5. MRP4 and prostaglandins -- 2.6. Leukotrienes in hematopoietic cells -- 2.7. MRP1 and leukotrienes -- 2.8. Porphyrin and ABCG2 -- 2.9. ABC transporters and AML -- 3. Kinases Impact Transporter Location and Function -- 3.1. Kinases and ABC transporters -- 3.2. Serine/threonine kinases Pim-1 and Akt affect ABCG2 location -- 3.3. Casein kinase 2 modulates MRP1 function -- 4. Future Perspective -- Acknowledgments -- References -- Chapter 7: Critical Role of ABCG2 in ALA-Photodynamic Diagnosis and Therapy of Human Brain Tumor -- 1. Introduction -- 2. Biosynthesis and Transport of Porphyrins -- 3. Enforced Biosynthesis of Protoporphyrin IX in Cancer Cells by ALA Administration -- 4. PDD and Fluorescence-Guided Microsurgery -- 5. Oxidative Stress-Mediated Gene Expression in PDT -- 6. Role of ABCG2 in PDT -- 7. Mechanism of ABCG2 Inhibition by Gefitinib -- 8. The Effect of Gefitinib on ALA-PDT in Brain Tumor U87MG Cells In Vitro -- 9. The Effect of Gefitinib on ALA-PDT in Xenograft Model -- 10. Concluding Remarks -- Acknowledgments -- References -- Chapter 8: Role of ABC Transporters in Fluoropyrimidine-Based Chemotherapy Response -- 1. Introduction: The Use of Fluoropyrimidines in Cancer Chemotherapy -- 1.1. Introduction -- 1.2. Pharmacokinetics of 5-FU -- 1.3. Pathways of fluoropyrimidine metabolism and mechanism of action.

1.4. Limitations of fluoropyrimidine-based therapy: Toxicity and resistance -- 2. Overview of Transporters Involved in Cellular Uptake and Efflux of Fluoropyrimidines and Their Metabolites -- 2.1. Uptake transporters -- 2.2. Efflux transporters -- 2.3. Other transport mechanisms -- 3. Cell-Based Evidence for the Role of ABC Transporters in 5-FU Pathways -- 3.1. ABCB1 -- 3.2. ABCB5 -- 3.3. ABCC1 -- 3.4. ABCC2 -- 3.5. ABCC4 -- 3.6. ABCC5 -- 3.7. ABCC11 -- 3.8. ABCG2 -- 4. Association of ABC Transporter Expression with Resistance in Clinical Specimens -- 4.1. ABCB1 -- 4.2. ABCB5 -- 4.3. ABCC1 -- 4.4. ABCG2 -- 4.5. Combined analyses of ABC transporters -- 5. Genotype-Phenotype Correlations of ABC Transporters and Fluoropyrimidine-Based Therapy Response -- Acknowledgments -- References -- Index -- Color Plate.

Description based on publisher supplied metadata and other sources.

Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, 2024. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries.