<P></P>
<P>Chapter 1. Classification of anticancer drugs based on therapeutic targets</P>
<P>Enrique Espinosa, César Gómez Raposo</P>
<P></P>
<P>
<P>Section</P>
<P>Contents</P>
<P>Abstract</P>
<P>1</P>
<P>Introduction</P>
<P>2</P>
<P>Drugs directed against tumour dna</P>
<P>2.1</P>
<P>Drugs directly affecting DNA helix: alkylators</P>
<P>2.2</P>
<P>Inhibitors of DNA-related proteins</P>
<P>2.2.1</P>
<P>Topoisomerases inhibitors</P>
<P>2.2.2</P>
<P>Antimetabolites</P>
<P>2.2.3</P>
<P>Histone related enzymes</P>
<P>2.2.4</P>
<P>Inhibitors of transcription factors</P>
<P>2.3</P>
<P>Specific genes</P>
<P>3</P>
<P>Drugs directed against tumour RNA</P>
<P>4</P>
<P>Drugs directed against proteins in the tumour cell</P>
<P>4.1</P>
<P>Receptors in the tumour membrane</P>
<P>4.2</P>
<P>Intracellular pathways in tumour cells</P>
<P>4.3</P>
<P>Tubulin</P>
<P>5</P>
<P>Drugs acting on the endothelium</P>
<P>5.1</P>
<P>Inhibition of pro-angiogenic factors</P>
<P>5.2</P>
<P>Inhibition of vascular receptors</P>
<P>5.3</P>
<P>Inside the endothelium</P>
<P>6</P>
<P>Drugs directed against extracellular matrix</P>
<P>6.1</P>
<P>Matrix metalloproteinases inhibitors</P>
<P>6.2</P>
<P>Anti-integrin therapy</P>
<P>6.3</P>
<P>Copper chelators</P>
<P>6.4</P>
<P>L1-CAM protein</P>
<P>6.5</P>
<P>Thrombospondin and others</P>
<P>7</P>
<P>Immunotherapy</P>
<P>7.1</P>
<P>Antibody-based immunotherapy of cancer</P>
<P>7.1.1</P>
<P>Unconjugated monoclonal antibodies</P>
<P>7.1.2</P>
<P>Conjugated monoclonal antibodies</P>
<P>7.1.3</P>
<P>Monoclonal antibodies as immunogens </P>
<P>7.2</P>
<P>Cytokines in cancer immunotherapy</P>
<P>7.3</P>
<P>Cancer vaccines</P>
<P>7.3.1</P>
<P>Peptide vaccines</P>
<P>7.3.2</P>
<P>Dendritic cell-based cancer vaccines</P>
<P>7.3.3</P>
<P>Cellular vaccines</P>
<P>7.3.4</P>
<P>DNA vaccines </P>
<P>7.3.5</P>
<P>Heat shock protein vaccines </P>
<P>7.4</P>
<P>Adoptive TCell transfer for cancer immunotherapy</P>
<P>7.5</P>
<P>Natural killer cell-based immunotherapy</P>
<P>7.6</P>
<P>Regulatory cells and cancer immunotherapy</P>
<P>7.7</P>
<P>Toll-like receptors</P>
<P>8</P>
<P>Drugs acting on potentially metastatic sites and glands</P>
<P>9</P>
<P>Conclusion</P>
<P>References</P>
<P>Figure legends</P>
<P>Tables</P>
<P></P>
<P></P>
<P> </P>
<P>Chapter 2. Signal transduction pathways as therapeutic targets in cancer therapy</P>
<P>Michele Milella, Ludovica Ciuffreda, Emilio Bria</P>
<P></P>
<P>
<P>Section</P>
<P>Contents</P>
<P>Abstract</P>
<P>1</P>
<P>Introduction</P>
<P>2</P>
<P>Protein tyrosine kinases (TK) as therapeutic targets</P>
<P>2.1</P>
<P>RTK as therapeutic targets: the paradigm of EGFR mutations in NSCLC</P>
<P>3</P>
<P>Cytoplasmic signaling intermediates</P>
<P>3.1</P>
<P>The Ras/Raf/MAPK pathway</P>
<P>3.2</P>
<P>The PI3K/AKT/mTOR pathway</P>
<P>3.3</P>
<P>Signaling crosstalk</P>
<P>4</P>
<P>Oncogenic addiction</P>
<P>4.1</P>
<P>Oncogenic shock</P>
<P>4.2</P>
<P>Oncogene amnesia</P>
<P>5</P>
<P>Open issues in the clinical development of signal transduction-targeted anticancer agents</P>
<P>5.1</P>
<P>The role of ‘early phases’: are phase II studies still necessary?</P>
<P>5.2</P>
<P>Phase II randomized studies: a new tale with targeted agents</P>
<P>5.3</P>
<P>Targeted agents: moving into phase III</P>
<P></P>
<P></P>
<P> </P>
<P>Chapter 3. HPMA-anticancer drug conjugates</P>
<P>Rihova B, Hovorka O, Kovar L, Kovar M, Mrkvan T, Sirova M, Ulbrich K</P>
<P></P>
<P>
<P>Section</P>
<P>Contents</P>
<P>Abstract</P>
<P>1.</P>
<P>Introduction</P>
<P>2.</P>
<P>Synthesis and structure of N-(2-hydroxypropyl)methacrylamide copolymer-drug conjugates</P>
<P>2.1</P>
<P>Synthesis of linear polymer-drug conjugates</P>
<P>2.2</P>
<P>Polymer conjugates with biologically activeproteins</P>
<P>2.3</P>
<P>Polymer systems designed for targeted drug delivery</P>
<P>2.3.1</P>
<P>Passively targeted HPMA copolymer-drug conjugates</P>
<P>2.3.1.1</P>
<P>Branched and grafted high-molecular-weight HPMA copolymer conjugates </P>
<P>2.3.1.2</P>
<P>Self-assembled and micellar structures</P>
<P>2.3.2</P>
<P>Actively targeted HPMA copolymer-drug conjugates</P>
<P>2.3.2.1</P>
<P>Antibody-targeted HPMA copolymer conjugates</P>
<P>2.3.2.2</P>
<P>Lectin -targeted HPMA copolymer conjugates</P>
<P>2.3.2.3</P>
<P>Oligopeptide-targeted HPMA copolymer conjugates</P>
<P>2.3.2.4</P>
<P>HPMA copolymer conjugates targeted with other low-molecular weight moieties</P>
<P>3.</P>
<P>Immunogenicity of HPMA-based conjugates</P>
<P>3.1</P>
<P>The humoral response against HPMA</P>
<P>3.2</P>
<P>The cellular response to HPMA</P>
<P>3.3</P>
<P>Complement activation</P>
<P>3.4</P>
<P>The chronic treatment</P>
<P>3.5</P>
<P>The decreased immunogenicity of proteins bound to HPMA</P>
<P>3.6</P>
<P>Decrease of side toxicity of HPMA-copolymer carrier bound drugs</P>
<P>4.</P>
<P>HPMA copolymer–doxorubicin conjugates with pH-controlled activation</P>
<P>4.1</P>
<P>Linear Dox-HPMA<SUP>HYD</SUP> conjugates</P>
<P>4.2</P>
<P>Branched and grafted Dox-HPMA<SUP>HYD</SUP> conjugates</P>
<P>4.3</P>
<P>Micellar Dox-HPMA<SUP>HYD</SUP> conjugates</P>
<P>4.4</P>
<P>Antibody-targeted Dox-HPMA<SUP>HYD</SUP> conjugates</P>
<P>4.5</P>
<P>Immunomodulatory properties of Dox-HPMA<SUP>HYD</SUP> conjugates</P>
<P>5.</P>
<P>HPMA copolymer doxorubicin conjugates with amide bond between the drug and carrier</P>
<P>5.1</P>
<P>Dox-HPMA<SUP>AM</SUP> (PK1)</P>
<P>5.2</P>
<P>Dox-HPMA<SUP>AM</SUP> conjugate containing human immunoglobulin (HuIg)</P>
<P>5.2.1</P>
<P>Preclinical evaluation of Dox-HPMA<SUP>AM</SUP>-HuIg </P>
<P>5.2.2</P>
<P>Pilot clinical study with Dox-HPMA<SUP>AM</SUP>-HuIg</P>
<P>5.3</P>
<P>HPMA-based polymer prodrugs in clinicaltrials</P>
<P>6.</P>
<P>Specific targeting of HPMA copolymer-bound drug conjugates to cancer cells</P>
<P>6.1</P>
<P>Targeting to asialoglycoprotein receptor</P>
<P>6.2</P>
<P>Targeting using lectins </P>
<P>6.3</P>
<P>Targeting using antibodies</P>
<P>6.4</P>
<P>Targeting to transferrin receptor</P>
<P>6.5</P>
<P>Targeting using synthetic peptides</P>
<P>7.</P>
<P>Intracellular destiny of polymeric conjugates based on HPMA</P>
<P>7.1</P>
<P>Lysosomotropic delivery of the polymeric drugs</P>
<P>7.2</P>
<P>Intracellular destiny of polymeric drugs</P>
<P>7.3</P>
<P>Effect of a doxorubicin derivative 7,8-dehydro-9,10-desacetyldoxorubicinone (D*) in the detection of fluorescence</P>
<P>7.4</P>
<P>The cleavability of conjugates </P>
<P>7.5</P>
<P>Apoptosis, necrosis and cell signalling</P>
<P>8.</P>
<P>Immunomodulatory properties of HPMA copolymer-bound doxorubicin</P>
<P></P>
<P></P>
<P> </P>
<P>Chapter 4. Poly-L-Glutamic acid anti-cancer drug conjugates</P>
<P>Jack W. Singer, Marc McKennon, Gabriella Pezzoni, Stefano di Giovine, Mara Cassin, Paola de Feudis, Cecilia Allievi, Patrizia Angiuli, Marco Natangelo, Enrico Vezzali, and Stefano Fazioni</P>
<P></P>
<P>
<P>Section</P>
<P>Contents</P>
<P>Abstract</P>
<P>1.</P>
<P>Introduction</P>
<P>2.</P>
<P>CT-2103 (Paclitaxel Poliglumex)</P>
<P>2.1</P>
<P>Chemistry and Manufacturing</P>
<P>2.1.1.</P>
<P>Technical Issues in the synthesis of CT-2103</P>
<P>2.1.2.</P>
<P>Synthetic strategy</P>
<P>2.1.3.</P>
<P>Synthesis Optimization</P>
<P>2.1.4.</P>
<P>Formulation of CT-2103</P>
<P>2.1.5.</P>
<P>Development of analytic methods and characterization of CT-2103</P>
<P>2.1.6.</P>
<P>Setting molecular weight and loading limits, the four corners approach</P>
<P>2.2.</P>
<P>Preclinical Pharmacology</P>
<P>2.2.1.</P>
<P>Pharmacokinetics</P>
<P>2.2.2.</P>
<P>Tissue distribution in rats and dogs</P>
<P>2.2.3.</P>
<P>Tissue distribution in comparison with paclitaxel in tumor bearing mice: </P>
<P>2.2.4.</P>
<P>Mass balance in rat</P>
<P>2.2.5.</P>
<P>Toxicology studies</P>
<P>2.3.</P>
<P>Cellular pharmacology </P>
<P>2.3.1.</P>
<P>Cellular Metabolism</P>
<P>2.3.2.</P>
<P>The role of the macrophage </P>
<P>2.3.3.</P>
<P>Preclinical efficacy </P>
<P>2.3.4.</P>
<P>In vivo efficacy studies in combination with radiation</P>
<P>2.3.5.</P>
<P>The effect of estradiol on CT-2103</P>
<P>2.4.</P>
<P>Preclinical Summary </P>
<P>2.5.</P>
<P>Clinical studies</P>
<P>2.5.1.</P>
<P>Phase I Studies: Determination of a safe and effective dose </P>
<P>2.5.2.</P>
<P>Phase II Studies</P>
<P>2.6.</P>
<P>Use of CT-2103 as a radiosensitizer</P>
<P>2.7.</P>
<P>Phase III Programs</P>
<P>2.7.1</P>
<P>Non-small cell lung cancer (NSCLC)</P>
<P>2.7.2.</P>
<P>Ovarian Cancer</P>
<P>3.</P>
<P>CT-2106 (poly-L-glutamic acid gly-camptothecin)</P>
<P>3.1.</P>
<P>Design and Synthesis</P>
<P>3.2.</P>
<P>Overview of preclinical studies</P>
<P>3.3.</P>
<P>Phase I Clinical Studies</P>
<P></P>
<P></P>
<P> </P>
<P> </P>
<P>Chapter 5. Polysaccharide-based anticancer prodrugs</P>
<P>Paolo Caliceti, Stefano Salmaso and Sara Bersani </P>
<P></P>
<P>
<P>Section</P>
<P>Contents</P>
<P>Abstract</P>
<P>1.</P>
<P>Introduction</P>
<P>2.</P>
<P>Chitin and Chitosan </P>
<P>2.1</P>
<P>Mitomycin C</P>
<P>2.1.1</P>
<P>Insoluble Suc-Chitosan-MMC derivatives</P>
<P>2.1.2</P>
<P>Soluble MMC-Suc-Chitosan derivatives</P>
<P>2.1.3</P>
<P>Lactosyl-Suc-Chitosan-MMC derivatives</P>
<P>2.2</P>
<P>Epirubcin</P>
<P>2.3</P>
<P>Doxorubicin</P>
<P>2.4</P>
<P>1-ß -D-arabinofuranosylcytosine</P>
<P>2.5</P>
<P>5-fluorouracil</P>
<P>2.6</P>
<P>Tyr-Ile-Gly-Ser-Arg</P>
<P>2.7</P>
<P>DNA</P>
<P>3.</P>
<P>Hyaluronic Acid</P>
<P>3.1</P>
<P>Paclitaxel</P>
<P>3.2</P>
<P>Doxorubicin</P>
<P>3.3</P>
<P>Butyric acid</P>
<P>3.4</P>
<P>All-Trans RetinoicAcid</P>
<P>4.</P>
<P>Dextran</P>
<P>4.1</P>
<P>Doxorubicin</P>
<P>4.2</P>
<P>Daunomycin</P>
<P>4.3 </P>
<P>Adriamycin</P>
<P>4.4</P>
<P>Mitomycin C</P>
<P>4.5</P>
<P>Paclitaxel</P>
<P>4.6</P>
<P>1-ß-D-arabinofuranosylcytosine</P>
<P>4.7</P>
<P>Cisplatin</P>
<P>4.8</P>
<P>Camptothecin</P>
<P>4.9</P>
<P>Methylprednisolone and Tacrolimus</P>
<P>4.10</P>
<P>Radionuclides</P>
<P>4.11</P>
<P>Proteins</P>
<P>5.</P>
<P>Arabinogalactan</P>
<P>6.</P>
<P>Pullulan</P>
<P>7.</P>
<P>Cyclodextrins</P>
<P></P>
<P></P>
<P> </P>
<P> </P>
<P> </P>
<P>Chapter 6. PEG-anticancer drugs</P>
<P>Francesca Cateni, Marina Zacchigna </P>
<P></P>
<P>
<P>Section</P>
<P>Contents</P>
<P>Abstract</P>
<P>1</P>
<P>Introduction</P>
<P>1.1</P>
<P>Drug delivery using permanent PEGylation</P>
<P>1.2</P>
<P>Non permanently bonded PEG-drugs: PEG prodrugs</P>
<P>2</P>
<P>PEG-anticancer prodrugs</P>
<P>2.1</P>
<P>PEG-Paclitaxel</P>
<P>2.2</P>
<P>PEG-Camptothecin</P>
<P>2.3</P>
<P>PEG-Doxorubicin</P>
<P>2.4</P>
<P>PEG-Daunorubucin</P>
<P>2.5</P>
<P>PEG-Epirubicin</P>
<P>2.6</P>
<P>PEG-Ara-C</P>
<P>2.7</P>
<P>PEG-Gemcitabine</P>
<P>2.8</P>
<P>PEG-Platinum drugs</P>
<P>2.9</P>
<P>PEG-Methotrexate</P>
<P></P>
<P></P>
<P> </P>
<P>Chapter 7. Poly(ethylene glycol)-protein, peptide and enzyme conjugates</P>
<P>F.M.Veronese, G. Pasut, S.Drioli and G.M.Bonora</P>
<P></P>
<P>
<P>Section</P>
<P>Contents</P>
<P>Abstract</P>
<P>1</P>
<P>Introduction</P>
<P>2</P>
<P>PEG-proteins and peptides </P>
<P>2.1</P>
<P>Antibodies and antibody fragments </P>
<P>2.2</P>
<P>Granulocyte colony-stimulating factor </P>
<P>2.3</P>
<P>Interferons</P>
<P>2.4</P>
<P>Thrombopoietin or megakaryocyte growth and development factor </P>
<P>2.5</P>
<P>Anti-cancer peptides </P>
<P>3</P>
<P>PEG-enzymes </P>
<P>3.1</P>
<P>Arginase</P>
<P>3.2</P>
<P>Argininedeiminase</P>
<P>3.3</P>
<P>Asparaginase</P>
<P>3.4</P>
<P>Methioninase</P>
<P>3.5</P>
<P>Glutaminase</P>
<P>3.6</P>
<P>Uricase</P>
<P>3.7</P>
<P>Other anti-cancer enzymes</P>
<P></P>
<P></P>
<P> </P>
<P> </P>
<P> </P>
<P>Chapter 8. Lipid-based anticancer prodrugs</P>
<P>L. Harivardhan Reddy and Patrick Couvreur</P>
<P></P>
<P>
<P>S. No.</P>
<P>Contents</P>
<P>1</P>
<P>Introduction</P>
<P>2</P>
<P>Lipids applied in cancer treatment</P>
<P>2.1</P>
<P>Non-fatty acids</P>
<P>2.1.1</P>
<P>Cardiolipin</P>
<P>2.1.2</P>
<P>Ceramide</P>
<P>2.2</P>
<P>Fatty acids</P>
<P>2.2.1</P>
<P>Essential fatty acids (EFAs)</P>
<P>2.2.2</P>
<P>Omega-3 fatty acids</P>
<P>2.2.3</P>
<P>Conjugated Linoleic acids</P>
<P>2.2.4</P>
<P>Olive oil constituent</P>
<P>2.2.4.1</P>
<P>Oleic acid</P>
<P>2.2.4.2</P>
<P>Elaidic acid</P>
<P>2.2.4.3</P>
<P>Squalene</P>
<P>2.2.5</P>
<P>Miscellaneous fatty acids</P>
<P>2.2.5.1</P>
<P>Valproic acid</P>
<P>2.2.5.2</P>
<P>Butyrates</P>
<P>3</P>
<P>Anticancer lipid prodrugs</P>
<P>3.1</P>
<P>Antibiotic anticancer drug-lipid conjugates</P>
<P>3.1.1</P>
<P>Mitomycin C-lipid conjugates</P>
<P>3.1.2</P>
<P>Doxorubicin-lipid conjugates</P>
<P>3.2</P>
<P>Antimetabolite anticancer drug-lipid conjugates</P>
<P>3.2.1</P>
<P>Methotrexate-lipid conjugates</P>
<P>3.2.2</P>
<P>Nucleoside analogue anticancer drug-lipid conjugates</P>
<P>3.2.2.1</P>
<P>Ara C-lipid conjugates</P>
<P>3.2.2.2</P>
<P>Gemcitabine-lipid conjugates</P>
<P>3.2.2.3</P>
<P>Troxacitabine-lipid conjugates</P>
<P>3.3</P>
<P>Taxane-lipid conjugates</P>
<P>3.4</P>
<P>Others: Camptothecin alkaloids-lipid conjugates</P>
<P></P>
<P></P>
<P><BR></P>
<P>Chapter 9. Antibody-Cytotoxic Compound Conjugates for Oncology</P>
<P>Carol A. Vater and Victor S. Goldmacher</P>
<P></P>
<P>
<P>Section</P>
<P>Contents</P>
<P>Abstract</P>
<P>1</P>
<P>Introduction</P>
<P>2</P>
<P>Target selection</P>
<P>3</P>
<P>Antibody selection</P>
<P>4</P>
<P>Cytotoxic compounds used in Antibody-Cytotoxic compound Conjugates (ACCs<SUP>1</SUP>)</P>
<P>5</P>
<P>Antibody-cytotoxic compound linker strategies</P>
<P>6</P>
<P>ACCs in clinical development</P>
<P>7</P>
<P>Conclusions and future prospects</P>
<P></P>
<P></P>
<P> </P>
<P> </P>
<P>Chapter 10. Immunoconjugate anticancer therapeutics</P>
<P>Serengulam V. Govindan and David M. Goldenberg</P>
<P></P>
<P>
<P>Section</P>
<P>Contents</P>
<P>Abstract</P>
<P>1.</P>
<P>Introduction</P>
<P>2.</P>
<P>mAb forms for conjugates</P>
<P>2.1</P>
<P>Radionuclide conjugates</P>
<P>2.1.1</P>
<P>Radionuclides for RAIT</P>
<P>2.1.2</P>
<P>Therapy of hematological cancers</P>
<P>2.1.3</P>
<P>Therapy of solid cancers</P>
<P>2.1.3.1</P>
<P>As an adjuvant </P>
<P>2.1.3.2</P>
<P>Combination therapy</P>
<P>2.1.3.3</P>
<P>Locoregional application </P>
<P>2.1.3.4</P>
<P>Pretargeting</P>
<P>2.1.4</P>
<P>Quo vadis?</P>
<P>2.2</P>
<P>Antibody-drug conjugates</P>
<P>2.2.1</P>
<P>Drugs</P>
<P>2.2.2</P>
<P>Cleavable linker in drug conjugate design</P>
<P>2.2.2.1</P>
<P>Hydrazone-containing conjugates</P>
<P>2.2.2.2</P>
<P>Disulfide-containing conjugates</P>
<P>2.2.2.3</P>
<P>Conjugates with a cleavable-peptide </P>
<P>2.2.2.4</P>
<P>Ester linker</P>
<P>2.2.3</P>
<P>MAb conjugates: Homogeneity and site-specificity </P>
<P>2.3</P>
<P>Toxin conjugates </P>
<P>2.3.1</P>
<P>Plant and bacterial toxin conjugates</P>
<P>2.3.2</P>
<P>Ribonuclease conjugates </P>
<P>Conclusions</P>
<P></P>
<P></P>
<P> </P>
<P> </P>
<P>Chapter 11. Antibody directed enzyme prodrug therapy (ADEPT) for cancer</P>
<P>Surinder K Sharma and Kenneth D Bagshawe</P>
<P></P>
<P>
<P>Section</P>
<P>Contents</P>
<P>Abstract</P>
<P>1.</P>
<P>Introduction and Principles</P>
<P>2.</P>
<P>Antibodies and targets</P>
<P>3.</P>
<P>Enzymes</P>
<P>3.1</P>
<P>Mammalian enzymes including human </P>
<P>3.2</P>
<P>Non-mammalian enzymes</P>
<P>3.3</P>
<P>Catalytic Antibodies</P>
<P>4.</P>
<P>Prodrugs</P>
<P>5.</P>
<P>Carboxypeptidase G2</P>
<P>5.1</P>
<P>Antibody-Enzyme conjugates</P>
<P>5.1.1</P>
<P>Pre-Clinical Studies</P>
<P>5.1.2</P>
<P>Clinical studies</P>
<P>5.2</P>
<P>Fusion Proteins</P>
<P>6.</P>
<P>Immunogenicity</P>
<P>Conclusion</P>
<P></P>
<P></P>
<P> </P>
<P> </P>
<P>Chapter 12. EGFR-directed monoclonal antibodies</P>
<P>Roberto Bianco, Teresa Gelardi, Sonia Garofalo, Roberta Rosa, Giampaolo Tortora</P>
<P></P>
<P>
<P>Section</P>
<P>Contents</P>
<P>Abstract</P>
<P>1.</P>
<P>EGFR and cancer</P>
<P>2.</P>
<P>EGFR inhibitors as anticancer therapy</P>
<P>3.</P>
<P>Anti-EGFR monoclonal antibodies (MAbs)</P>
<P>3.1.</P>
<P>Cetuximab (IMC-225)</P>
<P>3.2. </P>
<P>Panitumumab (ABX-EGF)</P>
<P>3.3.</P>
<P>Matuzumab (EMD72000)</P>
<P>3.4.</P>
<P>Nimotuzumab (hR3)</P>
<P>3.5.</P>
<P>Zalutumumab</P>
<P>3.6.</P>
<P>MDX-447</P>
<P>3.7.</P>
<P>ch806</P>
<P>Conclusion</P>
<P></P>
<P></P>
<P></P>
<P> </P>
<P>Chapter 13. The Biology of the HER Family and Her2/neu Directed-Antibody</P>
<P>Jennifer K. Litton and Gabriel N. Hortobagyi</P>
<P></P>
<P>
<P>Section</P>
<P>Contents</P>
<P>Abstract</P>
<P>1.</P>
<P>Introduction</P>
<P>2.</P>
<P>The HER Family</P>
<P>3.</P>
<P>HER2 and Downstream Signaling Pathways</P>
<P>3.1</P>
<P>The PI3k/Akt/mammalian target of rapamycin (mTOR) Pathway</P>
<P>3.2</P>
<P>HER2 and PTEN</P>
<P>3.3</P>
<P>The Ras/Raf/mitogen-activated protein kinase (MAPK) Pathway</P>
<P>3.4</P>
<P>HER2 and Endocrine Receptors (ER)</P>
<P>3.5</P>
<P>HER2 and p27</P>
<P>4.</P>
<P>HER2 Targeted Antibodies</P>
<P>4.1</P>
<P>Trastuzumab</P>
<P>4.1.1</P>
<P>Trastuzumab and Metastatic Breast Cancer: single agent trastuzumab</P>
<P>4.1.2</P>
<P>Dosing of Trastuzumab</P>
<P>4.1.3</P>
<P>Trastuzumab and Chemotherapy for Metastatic Breast Cancer</P>
<P>4.1.4</P>
<P>Trastuzumab and Aromatase Inhibitors for Metastatic Breast Cancer</P>
<P>4.1.5</P>
<P>Trastuzumab and Adjuvant Therapy</P>
<P>4.1.6</P>
<P>Trastuzumab and Neoadjuvant Chemotherapy</P>
<P>4.1.7</P>
<P>Treating with Trastuzumab Beyond Progression</P>
<P>4.1.8</P>
<P>Trastuzumab and Cardiotoxicity</P>
<P>4.1.9</P>
<P>Mechanisms of Resistance</P>
<P>4.2</P>
<P>HER and PTEN/PI3k/Akt/mammalian target of rapamycin (mTOR) Pathway</P>
<P>4.3</P>
<P>Insulin-like growth factor-1 receptor </P>
<P>4.4</P>
<P>MUC4 Over-expression</P>
<P>4.5</P>
<P>HER2 Receptor truncation or mutations</P>
<P>5.</P>
<P>Novel HER Family-directed antibodies</P>
<P>5.1</P>
<P>Pertuzumab</P>
<P>5.2</P>
<P>Trastuzumab-DM1</P>
<P>5.3</P>
<P>HER2 monoclonal antibodies and nanoparticles in development:</P>
<P>Conclusion</P>
<P></P>
<P></P>
<P> </P>
<P>Chapter 14. Anti-Vascular Endothelial Growth Factor Monoclonal Antibodies</P>
<P>Ernest S. Han and Bradley J. Monk</P>
<P></P>
<P>
<P>S. No.</P>
<P>Contents</P>
<P>Abstract</P>
<P>1.1</P>
<P>Angiogenesis and Cancer</P>
<P>1.1.1</P>
<P>Biologic relevance of vascular endothelial growth factor in tumor angiogenesis</P>
<P>1.1.2</P>
<P>VEGF family and receptors</P>
<P>1.1.3</P>
<P>VEGF as a target for cancer therapy</P>
<P>1.2</P>
<P>VEGF Monoclonal antibodies and clinical experience</P>
<P>1.2.1</P>
<P>Bevacizumab</P>
<P>1.2.1.1</P>
<P>Pharmacology</P>
<P>1.2.1.2</P>
<P>Clinical experience</P>
<P>1.2.1.3</P>
<P>Side effects</P>
<P>1.2.2</P>
<P>VEGF Trap</P>
<P>1.2.2.1</P>
<P>Pharmacology</P>
<P>1.2.2.2</P>
<P>Clinical experience</P>
<P>1.2.3</P>
<P>HuMV833</P>
<P>1.2.3.1</P>
<P>Pharmacology</P>
<P>1.2.3.2</P>
<P>Clinical experience</P>
<P>1.3</P>
<P>VEGF receptor monoclonal antibodies</P>
<P>1.3.1</P>
<P>IMC-1121b</P>
<P>1.3.2</P>
<P>IMC-18F1</P>
<P>1.3.3</P>
<P>CDP791</P>
<P>1.4</P>
<P>Monoclonal antibodies to placental growth factor</P>
<1.5</P>
<P>Current issues emerging from anti-VEGF therapies</P>
<P>1.5.1</P>
<P>Biologic markers for dosing and efficacy</P>
<P>1.5.2</P>
<P>Resistance to Anti-VEGF therapy</P>
<P>1.6</P>
<P>Summary</P>
<P></P>
<P></P>
<P> </P>
<P> </P>
<P>Chapter 15. Monoclonal Antibody Therapy for Hematologic Malignancies</P>
<P>Kenneth A. Foon, Michael Boyiadzis, Samuel A. Jacobs</P>
<P></P>
<P>
<P>Section</P>
<P>Contents</P>
<P>Abstract</P>
<P>1.</P>
<P>Introduction</P>
<P>2.</P>
<P>Rituximab</P>
<P>2.1</P>
<P>Follicular Lymphoma</P>
<P>2.2</P>
<P>Marginal Zone B-Cell Lymphoma</P>
<P>2.3</P>
<P>Mantle Cell Lymphoma</P>
<P>2.4</P>
<P>Diffuse Large B-Cell Lymphoma</P>
<P>2.5</P>
<P>Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma</P>
<P>3.</P>
<P>90Y Ibritumomab Tiuxetan</P>
<P>4.</P>
<P>131I tositumomab</P>
<P>5.</P>
<P>Alemtuzumab</P>
<P>6.</P>
<P>Gemtuzumab Ozogamicin </P>
<P>7.</P>
<P>Ofatumumab</P>
<P>8.</P>
<P>AME-133v</P>
<P>9.</P>
<P>Epratuzumab</P>
<P>10.</P>
<P>CMC-544</P>
<P>11.</P>
<P>BL22</P>
<P>12.</P>
<P>Lumiliximab</P>
<P>13.</P>
<P>Galiximab</P>
<P>14.</P>
<P>SGN-40</P>
<P>15.</P>
<P>Bevacizumab</P>
<P>16.</P>
<P>CP-751,871</P>
<P>17.</P>
<P>Zanolimumab</P>
<P>18.</P>
<P>Limtuzumab</P>
<P>19.</P>
<P>IMC-EB10</P>
<P>20.</P>
<P>SGN-30</P>
<P>21.</P>
<P>Chimeric Anti-CD4 Monoclonal Antibody</P>
<P>22.</P>
<P>TRU-016 </P>
<P>23.</P>
<P>Milatuzumab</P>
<P>24.</P>
<P>Ipilimumab</P>
<P>Conclusion</P>
<P></P>
<P></P>
<P> </P>
<P>Chapter 16. Anticancer oligonucleotides</P>
<P>Anne Laure Ramon and Claude Malvy </P>
<P></P>
<P>
<P>Section</P>
<P>Contents</P>
<P>1.</P>
<P>Introduction</P>
<P>2.</P>
<P>Pre-clinical studies</P>
<P>2.1</P>
<P>Antisense oligonucleotides</P>
<P>2.1.1</P>
<P>Studies on bcl-2 proto oncogene</P>
<P>2.1.2</P>
<P>Studies on Raf kinases</P>
<P>2.1.3</P>
<P>Studies on Ras proteins</P>
<P>2.1.4</P>
<P>Studies on PKC-a
<P>2.2</P>
<P>Small interfering RNA</P>
<P>2.2.1</P>
<P>Studies on bcl-2 proto oncogene</P>
<P>2.2.2</P>
<P>Studies on Raf kinases</P>
<P>2.2.3</P>
<P>Studies on Ras proteins and PKC-a</P>
<P>2.3</P>
<P>Decoys</P>
<P>2.4</P>
<P>Aptamers</P>
<P>2.5</P>
<P>Ribozymes</P>
<P>2.5.1</P>
<P>Studies on bcl-2</P>
<P>2.5.2</P>
<P>Studies on Ras proteins</P>
<P>2.5.3</P>
<P>Studies on PKC-a</P>
<P>2.6</P>
<P>Discussion</P>
<P>2.6.1</P>
<P>Immunostimulation</P>
<P>2.6.2</P>
<P>Minimal active doses</P>
<P>2.6.3</P>
<P>Selectivity and off-target effects</P>
<P>3.</P>
<P>Clinical studies</P>
<P>3.1</P>
<P>Antisense oligonucleotides</P>
<P>3.1.1</P>
<P>Clinical trials on Bcl-2</P>
<P>3.1.2</P>
<P>Clinical trials on Raf kinase</P>
<P>3.1.3</P>
<P>Clinical trials on Ras</P>
<P>3.1.4</P>
<P>Clinical trials on PKC-a</P>
<P>3.2</P>
<P>Small interfering RNA</P>
<P>3.3</P>
<P>Ribozymes</P>
<P>3.4</P>
<P>Decoys</P>
<P>3.5</P>
<P>Discussion</P>
<P>4.</P>
<P>Conclusion</P>
<P></P>
<P></P>
<P> </P>
<P> </P>
<P>Chapter 17. New molecular therapeutic interventions: the case of breast cancers</P>
<P>Véronique Marsaud and Jack-Michel Renoir</P>
<P></P>
<P>
<P>Section</P>
<P>Contents</P>
<P>Abstract</P>
<P>1.</P>
<P>Introduction</P>
<P>2.</P>
<P>2. Estrogens, phytoestrogens and xenoestrogens</P>
<P>2.1</P>
<P>Biosynthesis of estrogens</P>
<P>2.2</P>
<P>Phytoestrogens and xenoestrogens</P>
<P>3.</P>
<P>Estrogen receptors </P>
<P>3.1</P>
<P>Structure</P>
<P>3.2</P>
<P>The classical genomic transactivation mechanisms</P>
<P>3.3.</P>
<P>Non-classical transactivation systems </P>
<P>3.4</P>
<P>Nuclear localization and nucleo-cytoplasmic shuttling</P>
<P>3.5</P>
<P>Estrogen receptors stability</P>
<P>4. </P>
<P>Estrogen Receptors in Breast cancers</P>
<P>4.1</P>
<P>Estrogen receptors in the normal mammary gland</P>
<P>4.1.1 </P>
<P>Estrogen receptor isotypes in breastcancers</P>
<P>4.1.2.</P>
<P>Classical anti-hormonal treatments</P>
<P>4.1.2.1</P>
<P>SERDs and SERDs</P>
<P>4.1.2.2</P>
<P>Aromatase inhibitors</P>
<P>4.1.2.3</P>
<P>Resistance</P>
<P>5.</P>
<P>Emergence of innovative strategies for specific targets</P>
<P>5.1</P>
<P>Apoptosis induction and Cell cycle inhibition</P>
<P>5.1.1</P>
<P>Apoptosis</P>
<P>5.1.2</P>
<P>Cdk inhibitors </P>
<P>5.1.3</P>
<P>Survivin</P>
<P>5.1.4</P>
<P>Nuclear factor-k B</P>
<P>5.1.5</P>
<P>Ubiquitine-proteasome system</P>
<P>5.1.6</P>
<P>Histone deacetylase inhibitors</P>
<P>5.1.7</P>
<P>Hsp90 inhibitors</P>
<P>5.1.8 </P>
<P>p53</P>
<P>5.1.9</P>
<P>Pi3K/Akt pathway</P>
<P>5.1.10</P>
<P>Farnesyl transferase inhibitors (FTI)</P>
<P>5.2</P>
<P>Vascular and angiogenesis inhibitors </P>
<P>5.3</P>
<P>Monoclonal antibodies and tyrosine kinase inhibitors for EGFR and Erb-B2</P>
<P>6.</P>
<P>Breast cancer and stem cells</P>
<P>6. 1.</P>
<P>Implication of stem cells in metastasis</P>
<P>6.2. </P>
<P>Targeting CD44 for breast cancer therapy</P>
<P>7.</P>
<P>Conclusion and future perspectives</P>
<P></P>