To investigate synergism in activity from combination of platinum compounds and that from combination between phytochemicals in ovarian tumour models

By

TABLE OF CONTENTS

CHAPTER 1: INTRODUCTION1

1.1.Cancer1

1.1.1 History of cancer3

1.1.2 Cancer types (Category)3

1.1.2.1 Ovarian Cancer A2780, A2780CisR and A2780ZD473R5

1.2.Causes of cancer13

1.3.Treatments of cancer (mainly combination chemotherapy)14

1.3.1 Chemotherapy15

1.4.Cell Survival and Cell Death16

1.4.1 Cell cycle17

1.4.2 Cell death19

1.4.3 Genes involved in cancer19

1.5.DNA structure and conformation21

1.6.Platinum-Based Anticancer Drugs25

1.6.1.Cisplatin: The first generation27

1.6.1.1 Chemical Properties29

1.6.1.2Anticancer Properties of Cisplatin32

1.6.1.3Cisplatin hydrolysis38

1.6.1.4. Mode of Action of Cisplatin: DNA binding42

1.6.1.5 Apoptosis46

1.6.2.Second and third generation49

1.6.3.Rule-breaker platinums50

1.6.3.1BBR3464, YH11, YH12, CH1, CH251

1.6.4.Mechanism of Resistance by Platinum-based Drugs53

1.6.4.1Reduced cellular accumulation56

1.6.4.2Increased efflux58

1.6.4.3Drug detoxification59

1.6.4.4Alteration in DNA repair mechanism59

1.6.4.5Malfunction of apoptosis61

1.6.4.6. Alteration in biochemical pathways and drug targets62

1.6.5 Plant Based Anticancer Drugs64

1.6.5.1. Taxol (acting as mitotic poison tumor active)65

1.6.5.2. Colchicine (acting as mitotic poison tumor active)65

1.6.5.3. EGCG (acting as antioxidant)65

1.6.5.4. Resveratrol (acting as antioxidant)66

1.6.5.5. Curcumin (acting as antioxidant)66

1.7.Rational of Research67

1.8.Research Objectives69

REFERENCES71

CHAPTER 1: INTRODUCTION

Cancer

A summarized by the World Health Organization, cancer leads to about 12% of human deaths, claiming more than 10,000,000 lives each year. In the United States, cancer is the second leading cause of death, being responsible for approximately one in every four deaths. Interestingly, it is believed that at least one-third of all cancers could be prevented. As such, primary and secondary prevention strategies are reasonable approaches to reduce the occurrence of this disease and subsequent deaths. Primary prevention strategies involve removing causative agents and other life style modi?cations that decrease the risk of cancer, as ex-empli?ed by smoking cessation and screening tests to detect precancerous lesions (Flora, 1998). The age-adjusted incidence rate was 12.7 per 100,000 women per year. These rates are based on cases diagnosed in 2005-2009 from 18 SEER geographic areas.

Incidence Rates by Race

Race/Ethnicity

Female

All Races

12.7 per 100,000 women

White

13.4 per 100,000 women

Black

9.8 per 100,000 women

Asian/Pacific Islander

9.8 per 100,000 women

American Indian/Alaska Native 

11.2 per 100,000 women

Hispanic

11.3 per 100,000 women

Unfortunately, not all causative agents are known, and other suspected carcinogens are too widespread to prevent all exposure. Secondary prevention, cancer chemoprevention, involves the use of nontoxic natural and/or synthetic agents to decrease the risk of malignant tumor development or spread. Cancer chemoprevention is a multidisciplinary ?eld of research that has evolved from numerous scientific observations. For example, epidemiologic studies have linked diets high in fresh fruits and vegetables to lower cancer rates. This dietary link is perhaps most strongly supported by studies reporting the cancer risk of migrants from areas of low incidence to high incidence (Sporn, 1991).

These studies demonstrated that the incidence of cancer among children of migrants is similar to that of the general population. Another important breakthrough has been the prevention of experimentally induced cancer in laboratory animals. It was subsequently postulated that dietary components, particularly speci?c nutrients and/or phytochemicals found in fruits and vegetables, could be used to prevent cancer in human beings. More recently, research in cancer biology has elucidated molecular mechanisms of cancer chemopreventive agents. Much of the theoretical basis for cancer chemoprevention is the understanding that cancer develops over time through the process of ...