Chemistry and Pharmacology of Anticancer Drugs


Incidence and MortalityTerminologyMetastasesDiagnosis and ScreeningTumorigenesis: The Formation of Cancer CellsThe Causes of CancerInternal FactorsMutationsEpigenetic ChangesModified Gene ExpressionCancer Stem CellsExternal FactorsVirusesBacterial InfectionsWorm InfectionsDirect Transmission of CancerChemicalsRadioactivityElectromagnetic RadiationEffects of Cancer TreatmentsHereditary FactorsTreatmentsSurgeryChemotherapyRadiotherapyChemoradiotherapyPhotodynamic Therapy (PDT)Biological AgentsAccessibility of Therapeutic Agents to Tumor CellsLimiting the Toxicity of Chemotherapeutic AgentsDose Scheduling and Cell CycleCo-Administration of Other AgentsNovel Formulations and ProdrugsLimiting Toxicity to Hair and NailsPharmacogenomic Markers of ToxicityInfertility Following Cancer TreatmentOverview of Mechanisms of Action of Chemotherapeutic AgentsDrug ResistanceCombination ChemotherapyUse of Additional Therapeutic AgentsCost of Cancer CareConclusionsThe Evolution of Anticancer TherapiesIntroductionThe Discovery of New Anticancer AgentsSources of Novel “Lead” MoleculesResearch Tools and Methodologies for Drug DiscoveryGenomic-Based MethodologiesGene Mutations as Potential Drug TargetsGene Hunting and DNA SequencingGenomics and ProteomicsProtein Structural StudiesChemical TechnologiesScreening MethodologiesIn Vivo ModelsDrug Resistance and Personalized ChronotherapyNatural Products as a Source of New Lead MoleculesCancer Stem CellsDrug Repurposing (or Drug Repositioning)Fragment-Based Drug DiscoveryAI in Drug DiscoveryFunding the Discovery of New Anticancer AgentsConclusions and the Future of Drug DiscoveryAntimetabolitesIntroductionDihydrofolate Reductase (DHFR) InhibitorsPralatrexate (FolotynTM)Thymidylate Synthase InhibitorsRaltitrexed (Tomudex™)Pemetrexed (AlimtaTM)Nolatrexed (ThymitaqTM)Purine AntimetabolitesMercaptopurine (Puri-NetholTM; 6MP)Tioguanine (LanvisTM)Fludarabine Phosphate (FludaraTM)Cladribine (Leustat™ and Litak™)Clofarabine (EvoltraTM)Nelarabine (AtrianceTM)Pyrimidine Antimetabolites-Fluorouracil (5-FU)Tegafur (UftoralTM)Gemcitabine (GemzarTM)Capecitabine (XelodaTM)Cytarabine (CytosarTM, AlexanTM, ARA-C)Azacitidine (VidazaTM)Decitabine (DacogenTM)Trifluridine & Tipiracil (LonsurfTM)Adenosine Deaminase InhibitorsPentostatin (NipentTM)Ribonucleotide Reductase InhibitorsHydroxycarbamide (HydreaTM)TriapineTezacitabineConclusionsAntitubulin AgentsIntroductionStructure of MicrotubulesMicrotubule DynamicsTubulin InhibitorsVinca AlkaloidsVinblastine (VelbeTM)Vincristine (OncovinTM)Vindesine (EldisineTM)Vinorelbine (NavelbineTM)Vinflunine (JavlorTM)Halichondrin B AnaloguesEribulin mesylate (HalavenTM)The TaxanesPaclitaxel (Taxol™, Abraxane™)Docetaxel (Taxotere™, Docecad™)Cabazitaxel (JevtanaTM)LarotaxelTPI 287MAC-321The EpothilonesIxabepilone (IxempraTM)Epothilones in Clinical DevelopmentUtidelone (Depoxythilone or UTD1)New Approaches to Targeting Microtubule-Related MechanismsNovel Targets of Mitotic MediatorsAurora Kinase InhibitorsPolo-Like Kinases (PLKs)Novel Tubulin-Interacting AgentsCevipabulin (TTI-237)ConclusionsNucleic Acids as Therapeutic Targets and AgentsIntroductionAlkylating AgentsMethylating AgentsDacarbazine (DTIC-DomeTM)Temozolomide (TemodalTM)ProcarbazineAlkylating AgentsTrabectedin (YondelisTM)Experimental Alkylating AgentsCross-Linking AgentsNitrogen MustardsAliphatic Nitrogen MustardsAromatic Nitrogen MustardsConjugated Nitrogen MustardsAziridinesThiotepa (TepadinaTM)Benzoquinone AnaloguesEpoxides (Treosulfan, OvastatTM)Methanesulfonates (MyleranTM, BusilvexTM)NitrosoureasLomustine (CCNU)Carmustine (BiCNUTM)Streptozotocin (ZanosarTM)Platinum ComplexesCisplatinCarboplatinOxaliplatinOther Cisplatin AnalogsCarbinolaminesCyclopropanesMitomycin-CSequence-Selective DNA Cross-Linking AgentsPBD Dimers (SJG-136)Cyclopropanepyrroloindole (CPl) Dimer (Bizelesin)Intercalating AgentsAnthracyclinesDoxorubicinDaunorubicinAclarubicinEpirubicinIdarubicinPirarubicinAnthracenesMitoxantrone (OnkotroneTM, NovantroneTM)Pixantrone (PixuvriTM)PhenoxazinesDactinomycin (Cosmegen LyovacTM)Topoisomerase InhibitorsTopoisomerase I InhibitorsTopotecan (HycamtinTM)IrinotecanTopoisomerase II InhibitorsEtoposideTeniposideAmsacrineEllipticineDNA-Cleaving AgentsBleomycinsEnediynesNeocarzinostatinCalicheamicinsEsperamicinDynemicin ANucleic Acid TargetingIntroductionDuplex DNA TargetingSmall MoleculesQuadruplex DNA TargetingTelomerase Targeting AgentsPromoter Quadruplex TargetingTranscription Factor InhibitionRNA-Targeting ApproachesIntroductionAntisense OligonucleotidesRNA Interference (RNAi)MicroRNA (miRNA)Backbone-Modified Nucleic AcidsRibozymesSmall Molecule RNA TargetingDNA-Repair InhibitorsIntroductionPARP InhibitorsATR InhibitorsATM InhibitorsEpigenetic-Based TherapiesIntroductionDNA Methyltransferase InhibitorsHistone Deacetylase InhibitorsRadio- and Chemo-Sensitizing and Protecting AgentsGene TherapyConclusionsSmall-Molecule Targeted TherapiesIntroductionProtein Kinase InhibitorsClassification of Protein KinasesFunctions of Protein KinasesMechanism of Signal TransferRegulation of Kinase Activity by DrugsRole of Protein Kinases in CancerDevelopment of Inhibitors of Protein and Receptor KinasesProtein Kinase Inhibitors in Clinical Use or DevelopmentHedgehog Pathway InhibitorsVismodegib (ErivedgeTM)Sonidegib (OdomzoTM)Glasdegib (DaurismoTM)TAK-441BMS-833923Cell-Cycle (CDK) InhibitorsPalbociclib (IbranceTM)Ribociclib (Kisqali™)Abemaciclib (VerzeniosTM)Trilaciclib (G1T-28)Vorucicub (P1446A-05)Proteasome InhibitorsBortezomib (VelcadeTM)Carfilzomib (KyprolisTM)Ixazomib (NinlaroTM)Salinosporamide APhosphatidylinositol 3-Kinase (PI3K/AKT/mTOR) Pathway InhibitorsPIK3 InhibitorsIdelalisib (ZydeligTM)Copanlisib (AliqopaTM)Duvelisib (CopiktraTM)Alpelisib (PiqrayTM)Other PI3K InhibitorsAKT (Protein Kinase B) InhibitorsmTOR InhibitorsEverolimus (AfinitorTM)Temsirolimus (ToriselTM)Apoptosis InhibitorsVenetoclax (VenclyxtoTM)HDM2-p53 Interaction InhibitorsIdasanutlin (RG7388)AMG-232RetinoidsTretinoin (VesanoidTM)Bexarotene (TargtretinTM)Alitretinoin (PanretinTM)Antimetastatic AgentsHeat Shock Protein (HSP) InhibitorsConclusionsAntibody-Based TherapiesIntroductionStrategies for the Use of Antibodies in Anticancer TherapiesAnatomy of AntibodiesTypes of Antibodies UsedFull-Size AntibodiesOther Antibody FormatsNomenclature of AntibodiesReasons for the Slow Emergence of Antibody-Based TherapiesProduction of AntibodiesIntroductionHybridoma TechnologyChimeric, Humanized, and Human AntibodiesTumor-Associated Antigen SelectionStrategies to Improve the Properties of AntibodiesGlycoMAbTM TechnologyBispecific AntibodiesAntibodies as Single Agents (Naked mAbs)Mechanism of Action of Naked mAbsAntibody-Dependent Cell-Mediated Cytotoxicity (ADCC)Complement-Dependent Cytotoxicity (CDC)Cell SignalingExamples of Approved Single (“Naked”) AntibodiesHER2 ReceptorVEGFR and VEGFEGFR ReceptorCD ReceptorsImmuno-oncological (IO) InhibitorsRANK ReceptorAntibodies in DevelopmentAntibody Conjugates (“Immunoconjugates”)Antibody-Drug Conjugates (ADCs)Antigen/Antibody Choice and InternalizationPayload Structure and PotencyLinker Structures and PropertiesConjugation and Loading of Payloads on AntibodyChemistry Manufacturing Control (CMC)Biodistribution of ADCsUse of Biomarkers to Guide ADC TherapyApproved ADCs and ImmunotoxinsAntibody-Radionuclide Conjugates (Radioimmunoconjugates)IntroductionDirectly Linked RadioisotopeChelate-Linked RadioisotopeOthers Radioimmunoconjugates in DevelopmentAntibody–Cytokine Conjugates (Immunocytokines)IntroductionCytokinesMechanism of Action of ImmunocytokinesExamples of Immunocytokines in Clinical DevelopmentAntibody-Nanoparticle Conjugates (Immunoliposomes)Cytotoxic AgentsRadioisotopesAntigenic ProteinGene TherapyAntibody-RNAi Conjugates (ARCs)Antibody-Directed Enzyme Prodrug Therapy (ADEPT)IntroductionCarboxypeptidase G2 (CPG2)-Based ADEPTBi-Specific AntibodiesIntroductionManufacture of BsMABsTypes of Bispecific AntibodiesTri-functional Antibodies (Triomabs)Bispecific T-Cell Engagers (BiTEs)Diabodies (Db)Bispecifics ApprovedBlinatumomab (Blincyto™)BsMAbs in DevelopmentBispecific Antibodies Drug Conjugates (ADCs)BsAb RadioimmunotherapiesConclusionEndocrine TherapiesIntroductionBreast CancerRole of Estrogen in Tumor GrowthIntroductionEstrogen Types and ActivitiesStructure of the Estrogen ReceptorSignal TransductionImpact of Estrogen on DiseaseOther Treatment OptionsEarly Breast CancerAdvanced Breast CancerMetastatic DiseaseSelective Estrogen Receptor Modulators and Degraders (SERMs and SERDs)IntroductionTriphenylethylene AnaloguesBenzothiophene AnaloguesSteroidal Anti-EstrogenAromatase InhibitorsProstate CancerIntroductionGonadotropin-Releasing Hormone (GnRH) AnaloguesGonadotropin-Releasing Hormone (GnRH)GnRH Agonist AnaloguesGnRH Antagonist AnaloguesAnti-AndrogensSteroidal Antiandrogens (SAAs)Non-Steroidal Anti-Androgens (NSAAs)Experimental Anti-Androgen AgentsNeuroendocrine Tumors (NETS)Somatostatin AnaloguesOctreotide (SandostatinTM)Lanreotide (SomatulineTM)Pasireotide (SigniforTM)Sex HormonesIntroductionEstrogen TherapyDiethylstilbestrol (DES)Ethinylestradiol (EE)Progestogen TherapyMedroxyprogesterone Acetate (ProveraTM)Megestrol Acetate (MegaceTM)Norethisterone (Primolut NTM, UtovlanTM)Gestonorone Caproate (DepostatTM, PrimostatTM)Mitotane (LysodrenTM)Sulfatase InhibitorsConclusionsImmunomodulatory TherapiesIntroductionCytokinesInterferonsInterferon Alfa (IFN-α)Interferon Gamma-1b (IFN-1b, ImmukinTM)InterleukinsInterleukin-2 (IL-2, Aldesleukin, Proleukin™)IL 12IL 21IL 15Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF)Sargramostim (marketed as Leukine™)VaccinesTypes of Cancer VaccinesApproved Cancer VaccinesProphylactic VaccinesTreatment VaccinesExperimental VaccinesProphylactic VaccinesTreatment VaccinesAdoptive Cell-Based TherapiesAdoptive Cell-Based Anticancer Therapies Based on T CellsAdoptive Cell-Based Anticancer Therapies Using Tumor Infiltrating Lymphocytes (TIL)Adoptive Cell-Based Anticancer Therapies Using Genetically Modified Peripheral Blood T CellsAdoptive Cell-Based Anticancer Therapies Using Other Immune Infiltrating CellsAdoptive Cell-Based Anticancer Therapies Using Natural Killer (NK) CellsAdoptive Cell-Based Anticancer Therapies Using Dendritic CellsAdoptive Cell-Based Anticancer Therapies Using MacrophagesSmall-Molecule Immunomodulatory AgentsThalidomide-Based AgentsThalidomide (ThalomidTM)Lenalidomide (RevlimidTM)Pomalidomide (PomalystTM, ImnovidTM)Plerixafor (MozobilTM)Mifamurtide (MepactTM)Imiquimod (Aldara™, Zyclara™)ConclusionsAlternative Tumor-Targeting StrategiesIntroductionVascular-Targeting StrategiesAntiangiogenic AgentsMonoclonal AntibodiesTyrosine Kinase InhibitorsThalidomide and Related AnaloguesVascular Disruptive Agents (VDAs)CombretastatinsFosbretabulinHypoxia-Based ApproachesMitomycinAQ4N (Banoxantrone)Enzyme-Based ApproachesAmino Acid Deprivation Therapy (AADT)Asparaginase (SpectrilaTM, ErwinaseTM, OncasparTM, ElsparTM)Pegargiminase (ADI-PEG 20)ArginaseAntibody-Directed Enzyme Prodrug Therapy (ADEPT)-Based ApproachesAntibody-Directed Enzyme Prodrug Therapy (ADEPT)GDEPT and VDEPTEnzyme Prodrug TherapyCofactor-Mediated Prodrug TherapyNanoparticles and Conjugate TechnologiesEnhanced Permeation and Retention (EPR) EffectApproved Nanotechnology-Based ProductsLiposomal Doxorubicin (CaelyxTM, DoxilTM, MyocetTM)nabTM-paclitaxel (AbrexaneTM)Liposomal Irinotecan (OnivydeTM)Liposomal Daunorubicin/Cytarabine (VyxeosTM)Novel Nanotechnology ApproachesInternal TriggersExternal TriggersNanobot TechnologyPhotoactivated TherapiesPorfimer Sodium (PhotophrinTM)Temoporfin (FoscanTM)δ-Aminolevulinic AcidMethyl Aminolevulinate (MetvixTM, MetvixiaTM)Photoactivated Antibody-Drug Conjugates (ADCs)Ultrasound Ablation ApproachesElectromagnetic ApproachesNear Infrared Activated NanoshellsMicrowave AblationRadioactive NanoparticlesIntracranial DeliveryGliadelTM Wafer ImplantsNanotechnology ApproachesMRI-Guided CathetersBoron Neutron Capture Therapy (BNCT)ConclusionsThe Precision Medicine Approach in OncologyIntroduction and BackgroundUses of Genomic InformationGenetic Variability and SNPsComponents of the Precision Medicine ApproachPharmacogenetics and PharmacogenomicsMetabolism and Its Effect on Drug Efficacy and ToxicityMetabonomicsBiomarkersEpigeneticsTechnologies in Personalized MedicineTechnologies AvailableGenome SequencingGene ExpressionFunctional GenomicsProteomicsToxicogenomicsMetabonomicsEmerging TechnologiesPeptidomicsHistomicsCirculating Cancer Cells (CTCs)Circulating Tumor Nucleic AcidsEpigeneticsMicrofluidics and Multiplexing TechnologiesBioinformatics Concepts and ToolsApplications of Precision Medicine in OncologyScreening for Risk of Disease DevelopmentProstate-Specific Antigen (PSA)Colorectal Cancer (CRC)Pancreatic CancerOvarian CancerBrain CancerBreast CancerOral Cancer (OC)Bladder CancerCervical CancerPredisposition Biomarker Assays (Predictive Genetic Tests for Cancer Risk)Biomarker Screening to Select Optimal TreatmentsIntroductionHER2 (Breast Cancer)PD-LI (IO Responsive Tumors)BRAF Mutations (Melanoma)EML4-ALK Mutations (Lung Cancer)EGFR Mutations (Lung Cancer)Androgen Receptor Mutations (Prostate Cancer)Hematological CancersPrognosis, Staging, and Risk of Disease ReoccurrenceBreast CancerProstate CancerColorectal CancerBiomarkers Used to Predict Toxicity of Chemotherapeutic AgentsIntroductionUGT1A1 (Irinotecan)Dihydropyrimidine Dehydrogenase (DPD) (Capecitabine and 5-FU)Thiopurine S-Methyltransferase [TPMT] for Purine AntimetabolitesAmpliChipTM CYP450 TestUse of Biomarkers in Drug DiscoveryUse of Biomarkers in Clinical TrialsChemosensitivity TestingNovel Technologies For Personalizing Drug DosingConclusions and the Future of Precision Medicine in OncologyChemopreventive AgentsIntroductionPotential Mechanisms of ChemopreventionEffect on Metabolic and Other EnzymesEffect on Cellular TransportReduction of Inflammatory ProcessesInduction of ApoptosisInduction of Cell-Cycle ArrestInhibition of Cellular ProliferationInhibition of Cellular Invasion and MetastasisInhibition of AngiogenesisEpigenetic ModificationsEffect on Glucose MetabolismEstrogen and Androgen ModulationChallenges Associated with the Evaluation of Chemopreventive AgentsVariability of the Contents of Phytochemicals in PlantsLimitations of In Vitro and In Vivo StudiesBioavailabilitySide EffectsSynergistic Effects of Mixtures of Chemopreventive AgentsLimitations of Retrospective Human StudiesClinical Evaluation of Chemopreventive AgentsNaturally Occurring Chemopreventive AgentsFlavonoids and Related CompoundsQuercetinApigeninTangeretinNaringinSilibininEpigallocatechin-3-gallate (EGCG)ChalconesXanthohumolXanthonesMangostinPhytoestrogensIsoflavonesCoumestansLignansEffect of Dietary Xenoestrogens on Breast Cancer TreatmentsAlkaloidsBerberineCapsaicinMatrinePiperineSanguinarineTetrandrineGlucosinolatesIndole-3-carbinolTerpenoidsMonoterpenoidsDiterpenoidsTriterpenoidsTetraterpenoidsCurcuminOrganosulfur CompoundsSulforaphaneAllicinErgothioneinePhenolic AcidsGallic AcidEllagic AcidCaffeic AcidRosmarinic AcidChlorogenic AcidAntioxidantsAscorbic Acid (Vitamin C)The “Mediterranean Diet”Oleic AcidOleocanthalCarotenoids (Tetraterpenoids)ResveratrolSynthetic Chemopreventive AgentsAspirinNSAIDsIbruprofenEstrogen InhibitorsMetabolic AgentsMetforminStatinsConclusions
 
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