1. Chemical Carcinogenesis Cao Yi Section of Toxicology

2. Section 1 General Aspects of Cancer

3. Historical Foundation In 1700, Ramazzini described the first example of occupational cancer. The high incidence of breast cancer among nuns celibate life( 独身主义）. 1775 Percivall Pott The occurrence of cancer of the scrotum chimney sweeps soot In 1895 Rehn The occurrence of bladder cancer aniline dye

4. Table 12.2 Proportions of Cancer Deaths Attributed to Various Different Factors Major Factors Best Estimate (%) Range of Acceptable Estimates (%) Diet 3510– 70 Tobacco3025– 40 Infection 10 1– ? Reproductive and sexual behavior 7 1– 13 Occupation42– 8 Geophysical factors32– 4 Alcohol3 2– 4 Pollution 2<1–5 Food additives 1 −5–2 Medicines 1 0.5 – 3 Industrial products1 <1–2 Unknown?? Source: Adapted from R. Doll and R. Peto, The Causes of Cancer, Oxford Medical Publications, 1981.

5. Basic Concept Carcinogenesis is the process through which cancer develops. Chemical carcinogenesis is the study of the mechanisms through which chemical carcinogens induce cancer and also involves the development/utilization of experimental systems aimed at determining whether a substance is a potential human carcinogen.

6. Basic Concept Cancer is not a single disease but a large group of diseases, all of which can be characterized by the uncontrolled growth of an abnormal cell to produce a population of cells that have acquired the ability to multiply and invade surrounding and distant tissues. It is this invasive characteristic that imparts its lethality on the host.

7. Basic Concept Cancer is the general name for a malignant neoplasm. In terms of cancer nomenclature 命名法, most adult cancers are carcinomas that are derived from epithelial cells (colon, lung, breast, skin, etc). Sarcomas are derived from mesenchymal （ mi “ ze ｎ kimel 间叶细胞的） tissues, while leukemias and lymphomas are derived from blood-forming cells and lymphoid tissue. Melanoma is derived from melanocytes 黑素细胞 and retinoblastoma 视网膜成神经细胞瘤, glioblastoma 成胶质细胞瘤, and neuroblastoma are derived from the stem cells of the retina, glia 神经胶质, and neurons, respectively

8. Neoplasm or Tumor A neoplasm or tumor is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with the normal tissue, and persists after cessation of the stimuli that evoked it. There are two basic types of neoplasms, termed benign and malignant.

9. Table 12.1 Some General Characteristics of Malignant and Benign Neoplasms BenignMalignant Generally slow growingMay be slow to rapid growing Few mitotic figuresNumerous mitotic figures Well-differentiated architecture, resembles that of parent tissue Some lack differentiation, disorganized; loss of parent tissue architecture Sharply demarcated mass that does not invade surrounding tissue Locally invasive, infiltrating into surrounding normal tissue No metastasesMetastases

10. Section 2 Mechanism of Chemical carcinogenesis

11. Parent, Proximate, and Ultimate Carcinogen Chemical carcinogens that require metabolism to exert their carcinogenic effect are called procarcinogens (precarcinogens).A parent carcinogen is a compound that must be metabolized in order to have carcinogenic activity; Metabolites between procarcinogens and ultimate carcinogens are proximate carcinogens The products that interact with cellular components and are responsible for carcinogenic activity are ultimate carcinogens.

12. DNA Adducts One of the most intriguing problems in chemical carcinogenesis is the chemical characterization of the covalent compounds derived from reactions between the ultimate metabolite of a chemical carcinogen and a macromolecule. The most nucleophilic site in DNA is the N7 position of guanine, and many carcinogens form covalent adducts at that site. Adducts formed with DNA exhibit stereospecific configurations Carcinogens adduct DNA by direct methylation, ethylation, higher alkylations or hydroxylation Adduct → mutation → failure of repair → carcinogenesis

13. DNA Repair and carcinogenesis

14. Mutation and Carcinogenesis

15. The Incidence of Most Cancers Increase Exponentially With Age

16. Most cancers are monoclonal in origin (derived from a single cell) and do not arise from a single critical mutation but from the accumulation of sequential critical mutations in relevant target genes within a single cell (Figure 12.2).

17. Mutation Is the Basis of Cancer Development How many mutaions are needed? How did the mutations happen? What kinds of gene are critical? The Incidence of Most Cancers Increase Exponentially With Age Mutation Is the Basis of Cancer Development

18. What kinds of gene are critical? Proto-oncogen Oncogen tumor suppressor gene

19. proto-oncogene and Oncogen 癌基因（ oncogene): 一类在自然和实验条件下具有诱发恶 性转化能力的潜在基因。是化学致癌物作用的主要靶分子。 癌基因的实质是一类被激活的基因，所指导合成的蛋白质能 够促成细胞恶性表型的形成。 原癌基因（ proto-oncogene): 机体内正常细胞所具有的能 致癌的遗传信息。正常情况下呈静止状态，对细胞无害且具 有重要的生物功能（调控细胞生长分化、促进细胞分裂、增 殖等）。原癌基因在进化过程中高度保守。 外源致癌因子作用于原癌基因使之发生突变而激活，即转变 成为癌基因，导致细胞癌变。

20. 正常细胞 正调节信号 （如 oncogene ） 促进细胞生长、增殖 负调节信号 （如 antioncogene ） 抑制增殖，促进分 化、成熟、 衰老和 凋亡

21. proto-oncogene and Oncogen Specific genes found in normal cells, termed proto- oncogenes, are involved in the positive regulation of cell growth and are frequently mutated in cancer. Mutational alteration of these proto-oncogenes can result in a gain of function, for example, the altered gene product can continually stimulate cell proliferation. Proto-oncogenes with gain-of-function mutations are now referred to as oncogenes.

22. anti-oncogen (tumor suppressor gene) 抑癌基因（ anti-oncogen) ：正常细胞分裂生长的负性 调节因子，其编码的蛋白质能够降低或抑制细胞分裂 活性。对细胞的生长、增殖、分化起负调节作用，即 抑癌作用。 tumor suppressor genes can be mutationally inactivated during carcinogenesis resulting in a loss of function. Tumor suppressor genes and the proteins they encode often function as negative regulators of cell growth. Tumor suppressor genes containing loss-of-function mutations encode proteins that are by and large inactive.

24. Oncogene and anti-oncogene A simple analogy can be made to the automobile; tumor suppressor genes are analogous to the brakes on the car while the proto-oncogenes are analogous to the accelerator pedal. Mutations within tumor suppressor genes inactivate the braking system while mutations in proto-oncogenes activate the acceleration system. Altering both the cellular brakes and cellular accelerator results in uncontrolled cell growth. In addition to the regulation in cell growth, some oncogenes and tumor suppressor genes can also impair the cells ability to undergo apoptosis or programmed cell death.

28. 3 Stages of Chemical carcinogenesis

29. Initiation/promotion Model of Chemical carcinogenesis. Chemical carcinogenesis in experimental models can be divided into at least three stages: termed initiation, promotion, and progression

30. Initiation results from a simple mutation in one or more cellular genes controlling key regulatory pathways of the cell. Promotion results from the selective functional enhancement of signal transduction pathways induced in the initiated cell and its progeny by the continuous exposure to the promoting agent. Progression results from continuing evolution of a basically unstable karyotype.

36. Chemicals — metabolism — genetic and epigenetic alternation — cancer

37. Epigenetic mechanism of carcinogenesis Genotoxic chemicals are chemicals that are capable of damaging or modifying DNA, whereas epigenetic carcinogens exert their oncogenic effect by means other than genotoxic action. This includes such indirect mechanisms as alteration in gene expression, immunosuppression, hormonal imbalances, cytotoxicity, cocarcinogenic action, and promoting effects.

38. Section 3 Classification of Carcinogen

39. Carcinogens are classified by the weight of evidence for carcinogenicity referred to as sufficient, limited, or inadequate based on both epidemiological studies and animal data.

40. Table 12.5 IARC and EPA Classification of Carcinogens IARCEPA 1 Group A Human carcinogens Sufficient evidence from epidemiological studies to support a causal association between exposure to the agents and cancer 2A Group B Probable human carcinogens Group B1 Limited epidemiological evidence that the agent causes cancer regardless of animal data Group B2 Inadequate epidemiological evidence or no human data on the carcinogenicity of the agent and sufficient evidence in animal studies that the agent is carcinogenic 2B Group C Possible human carcinogens Absence of human data with limited evidence of carcinogenicity in animals 3 Group D Not classifiable as to human carcinogenicity Agents with inadequate human and animal evidence of carcinogenicity or for which no data are available 4 Group E Evidence of noncarcinogenicity for humans Agents that show no evidence for carcinogenicity in at least two adequate animal tests in different species or in both adequate epidemiologic and animal studies