毒理学基础个人总结 Chapter 9 Chemical carcinogenesis

毒理学基础个人总结 Chapter 9 Chemical carcinogenesis

Chapter 9 Chemical carcinogenesis

Part 1 Introduction

1. Historical Background

? Chemical carcinogenesis has been noted for over 200 years.

? 1761, Hill found relation between tobacco snuff and nasal cancer

? 1775, Port identified scrotum cancer cases in soot-exposing chimney sweeps. ? 1895, Rehn discovered that bladder tumors occurred in aniline dye-exposing

workers (β-naphthylamine being the involved carcinogen).

? In modern times, dozen of chemicals and physical factors have been

identified as human carcinogens.

? Facing the ever increasing risk of tumor upon human beings, governments,

industries and academic institutions all over the world are now striving for prevention and treatment of various life-threatening tumors.

2. Fundamental Concepts

a. Carcinogenesis

? Is the process of cancer development

? Chemical carcinogenesis deals with both the mechanisms for carcinogens to

induce cancer and the experimental systems to detect unknown

carcinogens.

? Cancer here does not mean merely carcinoma originated from epithelial

tissues, but represent neoplasm of all types.

b. Carcinogen

It has been estimated that about 90% of human cancers are caused by environmental factors, predominantly chemical carcinogens.

Part 2 Mechanism of Chemical Carcinogenesis

1. Metabolism of Chemical Carcinogens in Relation to Carcinogenesis

? Most carcinogenic chemicals per se (by themselves) are inactive, they need metabolic activation before exerting biological effects.

? Important terms related to bioactivation：

a) Procarcinogen

b) Proximate carcinogen

c) Ultimate carcinogen

d) Direct acting carcinogen

2. Interaction with Macromolecules

? Covalent binding of the reactive metabolites of chemicals to macromolecules, such as DNA, which may lead to point mutations, frameshift mutations and other damages.

? These changes may or may not be persistent ― they can be reversed by error-free DNA repair or disappear by apoptosis of the involving cells,

otherwise mutations can be retained and expanded through cell division.

3. Oncogene Hypothesis(学说)

a. Mutation and Carcinogenesis

? Human cancers have been confirmed as due to the accumulation of

mutations in critical genes.

? Most cancers are monoclonal in origin and arise from the accumulation of

sequential critical mutations in relevant target genes within a single cell.

b. Oncogenes and Tumor Suppressors

? Two types of genes involved in oncogenic mutations.

? Proto-oncogenes per se are inactive, once mutated the coded proteins gain

enhanced function: stimulation of cell division.

? Tumor suppressor genes code for proteins to inhibit cell division; in case of

mutations the altered proteins expressed lose their tumor-suppressing

potential, leave the enhanced growth of cells unchecked.

? Mutations of other genes, such as that determine the invasion of

surrounding tissues and metastasis, may also be involved in cancer

development.

Oncogenes: Mutations causing Gain of Function___

Mutations that Activate Oncogenes___

? Point mutation, gene amplification, and translocation in mutated (activated) oncogenes are identified in human cancers

? Qualitative or quantitative changes for activation of oncogenes

? The mechanism of proto-oncogene activation is specific for each gene. Tumor Suppressors: Mutations Causing Loss of Function___

? Deleted genes have been identified in some human cancers, supposed to normally inhibit cancerous growth.

? Mutations lead to loss of functions of these genes, which are termed tumor suppressor genes.

Rb and p53 Regulation of Cell Division and Cell Death___

? Mutated p53 gene (its protein product has a molecular weight of 53 kDa) have been identified in the majority of human cancers.

? Some tumors contain deletions of both alleles of p53, so its loss of function mutations is regarded oncogenic, and this gene is classified as a tumor suppressor gene.

? Rb is also found to be a tumor suppressor gene; its normal function is to sequester growth-promoting transcription factors.

? Loss of Rb function can result in a failure to exit from cell cycle.

? The p53 protein normally provides a safeguard against inappropriate proliferation.

? Therefore, Rb and p53 cooperate to regulate cell differentiation, cell cycle, and apoptosis.

4. Dysregulation of Cell Cycle and Carcinogenesis

? Loss of cell cycle regulation is a characteristic of cancer, and uncontrolled cell divison is an essential basis for tumor growth.

? Two major points of regulation: G1/S and G2/M phase transitions

? Numerous proteins have been identified that stringently regulate the

transition points.

? CDKs, cyclin-dependent kinases, are conserved serine-threonine kinases,

phosphorylate and activate specific relulatory proteins that drive cell cycle progression.

? Activity of CDKs is controlled by three levels:

a. Activation by interaction between CDKs and cyclin (cyclin-CDK complexes) b. Phosphorylation/dephosphorylation of CDKs by kinases and phosphatases c. Expression of CDKs is inhibited by CDK inhibitors (CKIs)

? Disturbance of tumor suppressor genes leads to unchecked cell proliferation.

Examples: a. Loss of function mutations of Rb gene, or functional inactivation of Rb by overexpression of INK4a. b. Mutation of p53 (appears in 50 % of

human cancers)

5. The Role of Telomerases in Cellular Immortalization and Development of Cancer

? Telomerases are a family of enzymes that are responsible for maintenance of the length of telomere, which progressively shorten until the cell dies by

apoptosis.

? Only germ cells and some neoplasic cells have telomerase activities and sustained function of the telomere.

? Telomerase activation may play an important role in the development of neoplasia.

6. Non-mutagenic Mechanisms of Carcinogenesis

? suppression, endocrine disruption, and activation of peroxisome

proliferators.

? Epigenetic gene silencing: through methylation of promoter DNA &

translational repression?loss of gene function in cancer.

? Failure to terminate proliferation and enhanced mitotic activity.

Part 3 Multi-stage Progresses of Carconogenesis

Initiation, promotion, and progression stages.

? The first and third stages both involve structural alterations in DNA (mutations). ? The intermediate stage―promotion, does not involve gene mutations, instead