Medicinal Chemistry of Anticancer Drugs

Carmen Avendaño, J. Carlos Menéndez, Carmen Avendano, J. Carlos Menendez

• Publisher: Elsevier Science
• Year: 2015
• eBook ISBN: 9780444626677
• Edition: 2
• Topic: Physical Sciences
• Subtopic: Pharmacology

Medicinal Chemistry of Anticancer Drugs, Second Edition, provides an updated treatment from the point of view of medicinal chemistry and drug design, focusing on the mechanism of action of antitumor drugs from the molecular level, and on the relationship between chemical structure and chemical and biochemical reactivity of antitumor agents. Antitumor chemotherapy is a very active field of research, and a huge amount of information on the topic is generated every year. Cytotoxic chemotherapy is gradually being supplemented by a new generation of drugs that recognize specific targets on the surface or inside cancer cells, and resistance to antitumor drugs continues to be investigated. While these therapies are in their infancy, they hold promise of more effective therapies with fewer side effects. Although many books are available that deal with clinical aspects of cancer chemotherapy, this book provides a sorely needed update from the point of view of medicinal chemistry and drug design. - Presents information in a clear and concise way using a large number of figures - Historical background provides insights on how the process of drug discovery in the anticancer field has evolved - Extensive references to primary literature

Chapter 1

General Aspects of Cancer Chemotherapy

Abstract

Cancer is a collective term for a group of diseases characterized by the loss of control of cell growth and division, leading to a primary tumor that invades and destroys adjacent tissues and can be followed by metastasis. It is responsible for approximately 14.5% of all deaths worldwide, with its incidence increasing due to the aging of the population in most countries. Chapter 1 provides a general view of the field of cancer chemotherapy, beginning with a discussion of the processes involved in tumorigenesis, including the role of oncogenes. A discussion of the therapeutic relevance of early cancer diagnosis is followed by a brief history of cancer chemotherapy, from the early cytotoxic era to targeted therapy. A discussion of general aspects of anticancer drug discovery is given next, with emphasis on the problems that occur in converting hit molecules into “druggable” compounds—that is, into molecules with adequate pharmaceutical properties. Combination chemotherapies have been a mainstay in the treatment of disseminated malignancies because cancer is a multifactorial disease, and the issues associated with combination therapies and personalized anticancer treatments are discussed next. This is followed by brief accounts of the role of natural products and nanotechnology in cancer chemotherapy. Finally, the chapter concludes with a list, in tabular form, that summarizes the main drugs approved by the U.S. Food and Drug Administration for use as anticancer agents according to the chapter in which they first appear in the book.

Keywords

oncogenes

cancer immunotherapy

cancer biomarkers

cancer stem cells (CSCs)

combination anticancer therapy

personalized anticancer treatments

short hairpin RNAs (shRNAs)

history of cancer chemotherapy

cancer nanotechnology

FDA-approved anticancer drugs

Contents

1. Introduction: some general comments about cancer

2. Tumorigenesis and oncogenes: pharmacogenomics

3. Early diagnosis of cancer and its therapeutic relevance

4. A brief history of cancer chemotherapy

5. General comments about anticancer drug discovery

6. Combination therapy and personalized anticancer treatments

7. Natural products in cancer chemotherapy

8. A brief comment about cancer nanotechnology

9. Summary of FDA-approved anticancer drugs

References

1 Introduction: Some General Comments About Cancer

Cancer is a collective term used to describe a group of different diseases that are characterized by the loss of control of cell growth and division, leading to a primary tumor that invades and destroys adjacent tissues. It may also spread to other regions of the body through a process known as metastasis, which is the cause of 90% of cancer deaths. Cancer remains one of the most difficult diseases to treat and is responsible for approximately 14.5% of all deaths worldwide. This incidence is increasing due to the aging of the population in most countries, including those under development. Indeed, against a widely held belief, more than two-thirds of all cancer deaths occur in low- and middle-income countries, and the estimated increase in cancer incidence by 2030, compared with 2008, will be greater in low- (82%) and lower-middle-income countries (70%) compared with the upper-middle- (58%) and high-income countries (40%).¹

The creation in late 1971 of the U.S. National Cancer Program led by the National Cancer Institute (NCI) had as its most important consequence that the amount of basic science implied in these studies permitted the initial understanding of cancer development. Cancer has been redefined throughout the years,² and currently comprehensive views exist of how most cancers arise and function at the genetic and biochemical level. However, the cure of cancer continues to be a daunting objective³ because of the high mutation potential of tumor cells and the original heterogeneity in genetic alterations of tumors—properties that permit the relapse of patients following initial treatment success, which creates a pressing need for alternative agents that could be used as later lines of therapy. In fact, drug resistance is still a major problem in oncology and affects old therapies, new targeted drugs, and personalized cancer treatments.

2 Tumorigenesis and Oncogenes: Pharmacogenomics

Tumorigenesis is a multistep process whose steps reflect genetic alterations including small-scale changes in DNA sequences, such as point mutations; larger scale chromosomal aberrations, such as translocations, deletions, and amplifications; and changes that affect the chromatin structure and are associated with dysfunctional epigenetic control, such as aberrant methylation of DNA or acetylation of histones.⁴ Any of these genetic alterations confers one or another type of growth ad...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Foreword
• Preface
• Abbreviations
• Chapter 1: General Aspects of Cancer Chemotherapy
• Chapter 2: Antimetabolites That Interfere with Nucleic Acid Biosynthesis
• Chapter 3: Anticancer Drugs That Modulate Hormone Action
• Chapter 4: Anticancer Drugs Acting via Radical Species: Radiotherapy and Photodynamic Therapy of Cancer
• Chapter 5: DNA Alkylating Agents
• Chapter 6: Anticancer Drugs That Interact with the DNA Minor Groove
• Chapter 7: Other Anticancer Drugs Targeting DNA and DNA-Associated Enzymes
• Chapter 8: Epigenetic Therapy of Cancer
• Chapter 9: Anticancer Drugs Targeting Tubulin and Microtubules
• Chapter 10: Drugs That Inhibit Signaling Pathways for Tumor Cell Growth and Proliferation: Kinase Inhibitors
• Chapter 11: Other Nonbiological Approaches to Targeted Cancer Chemotherapy
• Chapter 12: Biological Therapy of Cancer
• Chapter 13: Drug Targeting in Anticancer Chemotherapy
• Chapter 14: Drugs That Modulate Resistance to Antitumor Agents
• Chapter 15: Cancer Chemoprevention
• Index