Macromolecular Anticancer Therapeutics

vaccines 

7.3.5

Heat shock protein vaccines 

7.4

Adoptive TCell transfer for cancer immunotherapy

7.5

Natural killer cell-based immunotherapy

7.6

Regulatory cells and cancer immunotherapy

7.7

Toll-like receptors

8

Drugs acting on potentially metastatic sites and glands

9

Conclusion 

References 

Figure legends 

Tables





 

Chapter 2. Signal transduction pathways as therapeutic targets in cancer therapy

Michele Milella, Ludovica Ciuffreda, Emilio Bria





Section

Contents 

Abstract

1

Introduction

2

Protein tyrosine kinases (TK) as therapeutic targets

2.1

RTK as therapeutic targets: the paradigm of EGFR mutations in NSCLC

3

Cytoplasmic signaling intermediates

3.1

The Ras/Raf/MAPK pathway

3.2

The PI3K/AKT/mTOR pathway

3.3

Signaling crosstalk

4

Oncogenic addiction

4.1

Oncogenic shock

4.2

Oncogene amnesia

5

Open issues in the clinical development of signal transduction-targeted anticancer agents

5.1

The role of 'early phases': are phase II studies still necessary?

5.2

Phase II randomized studies: a new tale with targeted agents

5.3

Targeted agents: moving into phase III





 

Chapter 3. HPMA-anticancer drug conjugates

Rihova B, Hovorka O, Kovar L, Kovar M, Mrkvan T, Sirova M, Ulbrich K





Section

Contents 

Abstract

1.

Introduction

2.

Synthesis and structure of N-(2-hydroxypropyl)methacrylamide copolymer-drug conjugates

2.1

Synthesis of linear polymer-drug conjugates

2.2

Polymer conjugates with biologically activeproteins

2.3

Polymer systems designed for targeted drug delivery

2.3.1

Passively targeted HPMA copolymer-drug conjugates

2.3.1.1

Branched and grafted high-molecular-weight HPMA copolymer conjugates

2.3.1.2

Self-assembled and micellar structures

2.3.2

Actively targeted HPMA copolymer-drug conjugates

2.3.2.1

Antibody-targeted HPMA copolymer conjugates

2.3.2.2

Lectin -targeted HPMA copolymer conjugates

2.3.2.3

Oligopeptide-targeted HPMA copolymer conjugates

2.3.2.4

HPMA copolymer conjugates targeted with other low-molecular weight moieties

3.

Immunogenicity of HPMA-based conjugates

3.1

The humoral response against HPMA

3.2

The cellular response to HPMA

3.3

Complement activation

3.4

The chronic treatment

3.5

The decreased immunogenicity of proteins bound to HPMA

3.6

Decrease of side toxicity of HPMA-copolymer carrier bound drugs

4.

HPMA copolymer-doxorubicin conjugates with pH-controlled activation

4.1

Linear Dox-HPMAHYD conjugates

4.2

Branched and grafted Dox-HPMAHYD conjugates

4.3

Micellar Dox-HPMAHYD conjugates

4.4

Antibody-targeted Dox-HPMAHYD conjugates

4.5

Immunomodulatory properties of Dox-HPMAHYD conjugates

5.

HPMA copolymer doxorubicin conjugates with amide bond between the drug and carrier

5.1

Dox-HPMAAM (PK1)

5.2

Dox-HPMAAM conjugate containing human immunoglobulin (HuIg)

5.2.1

Preclinical evaluation of Dox-HPMAAM-HuIg

5.2.2

Pilot clinical study with Dox-HPMAAM-HuIg

5.3

HPMA-based polymer prodrugs in clinicaltrials

6.

Specific targeting of HPMA copolymer-bound drug conjugates to cancer cells

6.1

Targeting to asialoglycoprotein receptor

6.2

Targeting using lectins

6.3

Targeting using antibodies

6.4

Targeting to transferrin receptor

6.5

Targeting using synthetic peptides

7.

Intracellular destiny of polymeric conjugates based on HPMA

7.1

Lysosomotropic delivery of the polymeric drugs

7.2

Intracellular destiny of polymeric drugs

7.3

Effect of a doxorubicin derivative 7,8-dehydro-9,10-desacetyldoxorubicinone (D*) in the detection of fluorescence

7.4

The cleavability of conjugates

7.5

Apoptosis, necrosis and cell signalling

8.

Immunomodulatory properties of HPMA copolymer-bound doxorubicin





 

Chapter 4. Poly-L-Glutamic acid anti-cancer drug conjugates

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





Section

Contents 

Abstract

1.

Introduction

2.

CT-2103 (Paclitaxel Poliglumex)

2.1

Chemistry and Manufacturing

2.1.1.

Technical Issues in the synthesis of CT-2103

2.1.2.

Synthetic strategy

2.1.3.

Synthesis Optimization

2.1.4.

Formulation of CT-2103

2.1.5.

Development of analytic methods and characterization of CT-2103

2.1.6.

Setting molecular weight and loading limits, the four corners approach

2.2.

Preclinical Pharmacology

2.2.1.

Pharmacokinetics

2.2.2.

Tissue distribution in rats and dogs

2.2.3.

Tissue distribution in comparison with paclitaxel in tumor bearing mice:

2.2.4.

Mass balance in rat

2.2.5.

Toxicology studies

2.3.

Cellular pharmacology

2.3.1.

Cellular Metabolism

2.3.2.

The role of the macrophage

2.3.3.

Preclinical efficacy

2.3.4.

In vivo efficacy studies in combination with radiation

2.3.5.

The effect of estradiol on CT-2103

2.4.

Preclinical Summary

2.5.

Clinical studies

2.5.1.

Phase I Studies: Determination of a safe and effective dose

2.5.2.

Phase II Studies

2.6.

Use of CT-2103 as a radiosensitizer

2.7.

Phase III Programs

2.7.1

Non-small cell lung cancer (NSCLC)

2.7.2.

Ovarian Cancer

3.

CT-2106 (poly-L-glutamic acid gly-camptothecin)

3.1.

Design and Synthesis

3.2.

Overview of preclinical studies

3.3.

Phase I Clinical Studies





 

 

Chapter 5. Polysaccharide-based anticancer prodrugs

Paolo Caliceti, Stefano Salmaso and Sara Bersani





Section

Contents 

Abstract

1.

Introduction

2.

Chitin and Chitosan

2.1

Mitomycin C

2.1.1

Insoluble Suc-Chitosan-MMC derivatives

2.1.2

Soluble MMC-Suc-Chitosan derivatives

2.1.3

Lactosyl-Suc-Chitosan-MMC derivatives

2.2

Epirubcin

2.3

Doxorubicin

2.4

1-ß -D-arabinofuranosylcytosine

2.5

5-fluorouracil

2.6

Tyr-Ile-Gly-Ser-Arg

2.7

DNA

3.

Hyaluronic Acid

3.1

Paclitaxel

3.2

Doxorubicin

3.3

Butyric acid

3.4

All-Trans RetinoicAcid

4.

Dextran

4.1

Doxorubicin

4.2

Daunomycin

4.3

Adriamycin

4.4

Mitomycin C

4.5

Paclitaxel

4.6

1-ß-D-arabinofuranosylcytosine

4.7

Cisplatin

4.8

Camptothecin

4.9

Methylprednisolone and Tacrolimus

4.10

Radionuclides

4.11

Proteins

5.

Arabinogalactan

6.

Pullulan

7.

Cyclodextrins





 

 

 

Chapter 6. PEG-anticancer drugs

Francesca Cateni, Marina Zacchigna





Section

Contents 

Abstract

1

Introduction

1.1

Drug delivery using permanent PEGylation

1.2

Non permanently bonded PEG-drugs: PEG prodrugs

2

PEG-anticancer prodrugs

2.1

PEG-Paclitaxel

2.2

PEG-Camptothecin

2.3

PEG-Doxorubicin

2.4

PEG-Daunorubucin

2.5

PEG-Epirubicin

2.6

PEG-Ara-C

2.7

PEG-Gemcitabine

2.8

PEG-Platinum drugs

2.9

PEG-Methotrexate





 

Chapter 7. Poly(ethylene glycol)-protein, peptide and enzyme conjugates

F.M.Veronese, G. Pasut, S.Drioli and G.M.Bonora





Section

Contents 

Abstract

1

Introduction

2

PEG-proteins and peptides

2.1

Antibodies and antibody fragments

2.2

Granulocyte colony-stimulating factor

2.3

Interferons

2.4

Thrombopoietin or megakaryocyte growth and development factor

2.5

Anti-cancer peptides

3

PEG-enzymes

3.1

Arginase

3.2

Argininedeiminase

3.3

Asparaginase

3.4

Methioninase

3.5

Glutaminase

3.6

Uricase

3.7

Other anti-cancer enzymes





 

 

 

Chapter 8. Lipid-based anticancer prodrugs

L. Harivardhan Reddy and Patrick Couvreur





S. No.

Contents

1

Introduction

2

Lipids applied in cancer treatment

2.1

Non-fatty acids

2.1.1

Cardiolipin

2.1.2

Ceramide

2.2

Fatty acids

2.2.1

Essential fatty acids (EFAs)

2.2.2

Omega-3 fatty acids

2.2.3

Conjugated Linoleic acids

2.2.4

Olive oil constituent

2.2.4.1

Oleic acid

2.2.4.2

Elaidic acid

2.2.4.3

Squalene

2.2.5

Miscellaneous fatty acids

2.2.5.1

Valproic acid

2.2.5.2

Butyrates

3

Anticancer lipid prodrugs

3.1

Antibiotic anticancer drug-lipid conjugates

3.1.1

Mitomycin C-lipid conjugates

3.1.2

Doxorubicin-lipid conjugates

3.2

Antimetabolite anticancer drug-lipid conjugates

3.2.1

Methotrexate-lipid conjugates

3.2.2

Nucleoside analogue anticancer drug-lipid conjugates

3.2.2.1

Ara C-lipid conjugates

3.2.2.2

Gemcitabine-lipid conjugates

3.2.2.3

Troxacitabine-lipid conjugates

3.3

Taxane-lipid conjugates

3.4

Others: Camptothecin alkaloids-lipid conjugates








Chapter 9. Antibody-Cytotoxic Compound Conjugates for Oncology

Carol A. Vater and Victor S. Goldmacher





Section

Contents 

Abstract

1

Introduction

2

Target selection

3

Antibody selection

4

Cytotoxic compounds used in Antibody-Cytotoxic compound Conjugates (ACCs1)

5

Antibody-cytotoxic compound linker strategies

6

ACCs in clinical development

7

Conclusions and future prospects





 

 

Chapter 10. Immunoconjugate anticancer therapeutics

Serengulam V. Govindan and David M. Goldenberg





Section

Contents 

Abstract

1.

Introduction

2.

mAb forms for conjugates

2.1

Radionuclide conjugates

2.1.1

Radionuclides for RAIT

2.1.2

Therapy of hematological cancers

2.1.3

Therapy of solid cancers

2.1.3.1

As an adjuvant

2.1.3.2

Combination therapy

2.1.3.3

Locoregional application

2.1.3.4

Pretargeting

2.1.4

Quo vadis?

2.2

Antibody-drug conjugates

2.2.1

Drugs

2.2.2

Cleavable linker in drug conjugate design

2.2.2.1

Hydrazone-containing conjugates

2.2.2.2

Disulfide-containing conjugates

2.2.2.3

Conjugates with a cleavable-peptide

2.2.2.4

Ester linker

2.2.3

MAb conjugates: Homogeneity and site-specificity

2.3

Toxin conjugates

2.3.1

Plant and bacterial toxin conjugates

2.3.2

Ribonuclease conjugates  

Conclusions





 

 

Chapter 11. Antibody directed enzyme prodrug therapy (ADEPT) for cancer

Surinder K Sharma and Kenneth D Bagshawe





Section

Contents 

Abstract

1.

Introduction and Principles

2.

Antibodies and targets

3.

Enzymes

3.1

Mammalian enzymes including human

3.2

Non-mammalian enzymes

3.3

Catalytic Antibodies

4.

Prodrugs

5.

Carboxypeptidase G2

5.1

Antibody-Enzyme conjugates

5.1.1

Pre-Clinical Studies

5.1.2

Clinical studies

5.2

Fusion Proteins

6.

Immunogenicity 

Conclusion





 

 

Chapter 12. EGFR-directed monoclonal antibodies

Roberto Bianco, Teresa Gelardi, Sonia Garofalo, Roberta Rosa, Giampaolo Tortora





Section

Contents 

Abstract

1.

EGFR and cancer

2.

EGFR inhibitors as anticancer therapy

3.

Anti-EGFR monoclonal antibodies (MAbs)

3.1.

Cetuximab (IMC-225)

3.2.

Panitumumab (ABX-EGF)

3.3.

Matuzumab (EMD72000)

3.4.

Nimotuzumab (hR3)

3.5.

Zalutumumab

3.6.

MDX-447

3.7.

ch806 

Conclusion







 

Chapter 13. The Biology of the HER Family and Her2/neu Directed-Antibody

Jennifer K. Litton and Gabriel N. Hortobagyi





Section

Contents 

Abstract

1.

Introduction

2.

The HER Family

3.

HER2 and Downstream Signaling Pathways

3.1

The PI3k/Akt/mammalian target of rapamycin (mTOR) Pathway

3.2

HER2 and PTEN

3.3

The Ras/Raf/mitogen-activated protein kinase (MAPK) Pathway

3.4

HER2 and Endocrine Receptors (ER)

3.5

HER2 and p27

4.

HER2 Targeted Antibodies

4.1

Trastuzumab

4.1.1

Trastuzumab and Metastatic Breast Cancer: single agent trastuzumab

4.1.2

Dosing of Trastuzumab

4.1.3

Trastuzumab and Chemotherapy for Metastatic Breast Cancer

4.1.4

Trastuzumab and Aromatase Inhibitors for Metastatic Breast Cancer

4.1.5

Trastuzumab and Adjuvant Therapy

4.1.6

Trastuzumab and Neoadjuvant Chemotherapy

4.1.7

Treating with Trastuzumab Beyond Progression

4.1.8

Trastuzumab and Cardiotoxicity

4.1.9

Mechanisms of Resistance

4.2

HER and PTEN/PI3k/Akt/mammalian target of rapamycin (mTOR) Pathway

4.3

Insulin-like growth factor-1 receptor

4.4

MUC4 Over-expression

4.5

HER2 Receptor truncation or mutations

5.

Novel HER Family-directed antibodies

5.1

Pertuzumab

5.2

Trastuzumab-DM1

5.3

HER2 monoclonal antibodies and nanoparticles in development: 

Conclusion





 

Chapter 14. Anti-Vascular Endothelial Growth Factor Monoclonal Antibodies

Ernest S. Han and Bradley J. Monk





S. No.

Contents 

Abstract

1.1

Angiogenesis and Cancer

1.1.1

Biologic relevance of vascular endothelial growth factor in tumor angiogenesis

1.1.2

VEGF family and receptors

1.1.3

VEGF as a target for cancer therapy

1.2

VEGF Monoclonal antibodies and clinical experience

1.2.1

Bevacizumab

1.2.1.1

Pharmacology

1.2.1.2

Clinical experience

1.2.1.3

Side effects

1.2.2

VEGF Trap

1.2.2.1

Pharmacology

1.2.2.2

Clinical experience

1.2.3

HuMV833

1.2.3.1

Pharmacology

1.2.3.2

Clinical experience

1.3

VEGF receptor monoclonal antibodies

1.3.1

IMC-1121b

1.3.2

IMC-18F1

1.3.3

CDP791

1.4

Monoclonal antibodies to placental growth factor<1.5



Current issues emerging from anti-VEGF therapies

1.5.1

Biologic markers for dosing and efficacy

1.5.2

Resistance to Anti-VEGF therapy

1.6

Summary





 

 

Chapter 15. Monoclonal Antibody Therapy for Hematologic Malignancies

Kenneth A. Foon, Michael Boyiadzis, Samuel A. Jacobs





Section

Contents 

Abstract

1.

Introduction

2.

Rituximab

2.1

Follicular Lymphoma

2.2

Marginal Zone B-Cell Lymphoma

2.3

Mantle Cell Lymphoma

2.4

Diffuse Large B-Cell Lymphoma

2.5

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

3.

90Y Ibritumomab Tiuxetan

4.

131I tositumomab

5.

Alemtuzumab

6.

Gemtuzumab Ozogamicin

7.

Ofatumumab

8.

AME-133v

9.

Epratuzumab

10.

CMC-544

11.

BL22

12.

Lumiliximab

13.

Galiximab

14.

SGN-40

15.

Bevacizumab

16.

CP-751,871

17.

Zanolimumab

18.

Limtuzumab

19.

IMC-EB10

20.

SGN-30

21.

Chimeric Anti-CD4 Monoclonal Antibody

22.

TRU-016

23.

Milatuzumab

24.

Ipilimumab 

Conclusion





 

Chapter 16. Anticancer oligonucleotides

Anne Laure Ramon and Claude Malvy





Section

Contents

1.

Introduction

2.

Pre-clinical studies

2.1

Antisense oligonucleotides

2.1.1

Studies on bcl-2 proto oncogene

2.1.2

Studies on Raf kinases

2.1.3

Studies on Ras proteins

2.1.4

Studies on PKC-a

2.2

Small interfering RNA

2.2.1

Studies on bcl-2 proto oncogene

2.2.2

Studies on Raf kinases

2.2.3

Studies on Ras proteins and PKC-a

2.3

Decoys

2.4

Aptamers

2.5

Ribozymes

2.5.1

Studies on bcl-2

2.5.2

Studies on Ras proteins

2.5.3

Studies on PKC-a

2.6

Discussion

2.6.1

Immunostimulation

2.6.2

Minimal active doses

2.6.3

Selectivity and off-target effects

3.

Clinical studies

3.1

Antisense oligonucleotides

3.1.1

Clinical trials on Bcl-2

3.1.2

Clinical trials on Raf kinase

3.1.3

Clinical trials on Ras

3.1.4

Clinical trials on PKC-a

3.2

Small interfering RNA

3.3

Ribozymes

3.4

Decoys

3.5

Discussion

4.

Conclusion





 

 

Chapter 17. New molecular therapeutic interventions: the case of breast cancers

Véronique Marsaud and Jack-Michel Renoir





Section

Contents 

Abstract

1.

Introduction

2.

2. Estrogens, phytoestrogens and xenoestrogens

2.1

Biosynthesis of estrogens

2.2

Phytoestrogens and xenoestrogens

3.

Estrogen receptors

3.1

Structure

3.2

The classical genomic transactivation mechanisms

3.3.

Non-classical transactivation systems

3.4

Nuclear localization and nucleo-cytoplasmic shuttling

3.5

Estrogen receptors stability

4.

Estrogen Receptors in Breast cancers

4.1

Estrogen receptors in the normal mammary gland

4.1.1

Estrogen receptor isotypes in breastcancers

4.1.2.

Classical anti-hormonal treatments

4.1.2.1

SERDs and SERDs

4.1.2.2

Aromatase inhibitors

4.1.2.3

Resistance

5.

Emergence of innovative strategies for specific targets

5.1

Apoptosis induction and Cell cycle inhibition

5.1.1

Apoptosis

5.1.2

Cdk inhibitors

5.1.3

Survivin

5.1.4

Nuclear factor-k B

5.1.5

Ubiquitine-proteasome system

5.1.6

Histone deacetylase inhibitors

5.1.7

Hsp90 inhibitors

5.1.8

p53

5.1.9

Pi3K/Akt pathway

5.1.10

Farnesyl transferase inhibitors (FTI)

5.2

Vascular and angiogenesis inhibitors

5.3

Monoclonal antibodies and tyrosine kinase inhibitors for EGFR and Erb-B2

6.

Breast cancer and stem cells

6. 1.

Implication of stem cells in metastasis

6.2.

Targeting CD44 for breast cancer therapy

7.

Conclusion and future perspectives

and co-author, 341 publications, 109 review articles and book chapters, 6 books as editor, 50 patents, and 193 invited and plenary lectures at national and international congresses. He has received Pharmaceutical Sciences World Congress Award (2004), the "Marie-Maurice Janot Lecture" (2008) and above all the prestigious "Host Madsen Medal" (2007) in honour of his outstanding research achievements. He is a Field Editor of "Pharmaceutical Research", European Editor of the "Journal of Nanoparticles Research", and is a reviewer of more than 15 high reputed journals in the fields of Drug delivery, cancer research, macromolecules, physical chemistry etc. He is acting or acted as Board of Governors of the Controlled Release Society (CRS), Board of APGI, Expert Member of the Board of Pharmaceutical Sciences, International Pharmaceutical Federation (FIP). His exceptional research has led to two start-up companies BIOALLIANCE and MEDSQUAL dealing with novel therapeutics, in France.