**2. Summary of stages of chemical carcinogenesis**

Studies indicate that three stages of chemical carcinogenesis can be defined; initiation, promotion and progression as briefly alluded previously.

**Initiation:** This is concerned with the induction of genetic changes in cells, leading to genome instability. This can be accentuated by micronutrient deficiency disorders. The nature of the initial changes is still incompletely elucidated (Satoh, 1988)

**Promotion:** This largely involves the induction or commencement of cell proliferation. In this phase of carcinogenesis a promoting agent or enabling microenvironment, brings about increased cell proliferation. This stage is very important as it is reversible if the promoting agents or risk factor(s) are withdrawn. Probably also, if some genome stabilizing micronutrients are abundant. This stage has been exploited considerably for both therapeutic and chemopreventive measures that are in part dependent on micronutrients.

**Progression**: If cell proliferation is sustained then initiated cells acquire secondary genetic abnormalities in oncogenes which first lead to dysregulation and finally to autonomous growth characteristic of cancer. The ultimate end-point of progression is development of invasive neoplasm.

While many environmental agents can be considered to be chemical carcinogens; some act as both initiators and promoter (complete carcinogens). The understanding of molecular aspects of chemical carcinogenesis has lead to development of the concept of chemoprevention (anticarcinogenesis). This process proposes strategies for intervention at the phase of malignancy using drugs or natural or synthetic agents to reverse or halt the evolution of carcinogenesis which is dependent on recognition of risk factors and early detection.

## **2.1 Brief history of chemical carcinogenesis**

72 Biomedical Science, Engineering and Technology

Foulds (1969) suggested that cancer development consisted of three, rather than two processes: (1) initiation, or the conversion of normal cells to a potentially precancerous form (2) promotion, or the expansion of the clones of initiated cells to form tumors; and (3) progression, or the development of tumors to increasing levels of malignancy. The original view was based on Foulds' wealth of experience with both clinical and experimental cancer. It has however, been expanded greatly since it was first propounded by Foulds (1982). Other investigators have also made significant contributions to the understanding of the process of carcinogenesis by suggesting that there are two major cell-based processes essential to the formation of tumors (Ames and Gold, 1981).The first, or initiating stage, is due to mutation; alteration of the DNA of the affected cell through permanent modification of the DNA. These mutations take place at specific locations on the DNA, referred to as oncogenes and tumor suppressor genes, if these individual cells are to serve as precursors of cancer (Willis, 1960; Klein and Klein, 1984). This area remains intensely investigated in the last couple of decades. What is perhaps worthy of note is that while the activation of an oncogene requires mutation at a specific single base (arrangement of the amines making up the DNA) pair on the DNA template, inhibition of a tumor suppressor gene may be achieved by a much wider

In current research, emphasis is laid on the identification of the genes that are involved in the mutation and subsequent molecular events. The failure in the control mechanisms regulating the expression of and response to tissue growth factors is of considerable interest in chemical carcinogenesis. This contributes to the risk of chemical carcinogenesis and is in turn attributable to a number of factors that will be discussed subsequently. A critical process in carcinogenesis is promotion. This involves cellular proliferation, which involves the division of cells to form two unusually identical cells. This may increase the number of both "normal" and neoplastic mutated or preneoplastic cells, enhancing the chance of a tumor being expressed in a clinically observable form. Surprisingly, such increased levels of cellular proliferation may not be apparent in normal cells of a particular tissue but may occur only in pretumor cells thus making early detection difficult. Tumors are well known to increase in their degree of malignancy with time, a process named "progression" by Foulds. Cohen and Elwein (1991) have suggested that progression is the result of a cascade of further critical mutations in the neoplastic cell population followed by further cell proliferation to increase the number of genetically altered cells and the chance of their

Studies indicate that three stages of chemical carcinogenesis can be defined; initiation,

**Initiation:** This is concerned with the induction of genetic changes in cells, leading to genome instability. This can be accentuated by micronutrient deficiency disorders. The

**Promotion:** This largely involves the induction or commencement of cell proliferation. In this phase of carcinogenesis a promoting agent or enabling microenvironment, brings about increased cell proliferation. This stage is very important as it is reversible if the promoting agents or risk factor(s) are withdrawn. Probably also, if some genome stabilizing micronutrients are abundant. This stage has been exploited considerably for both therapeutic and chemopreventive measures that are in part dependent on micronutrients.

forming an increasingly malignant, clinically apparent cancer.

**2. Summary of stages of chemical carcinogenesis** 

promotion and progression as briefly alluded previously.

nature of the initial changes is still incompletely elucidated (Satoh, 1988)

range of damaging interactions.

The history of chemical carcinogenesis is punctuated by key epidemiologic observations and animal experiments that identified cancer-causing chemicals and that led to increasingly insightful experiments to establish molecular mechanisms and to reduction of human exposure to chemicals. In 1914, Boveri (1914) made key observations of chromosomal changes, including aneuploidy. His analysis of mitosis in frog cells and his extrapolation to human cancer is an early example of a basic research finding generating an important hypothesis (the somatic mutation hypothesis). The first experimental induction of cancer in rabbits exposed to coal tar was performed in Japan by Yamagiwa and Ichikawa (1918) and was a confirmation of Pott's epidemiologic observation of scrotal cancer in chimney sweeps in the previous century (Potts, 1775). Owing to the fact that coal tar is a complex mixture of chemicals, a search for specific chemical carcinogens was undertaken. British chemists, including Kennaway (1930), took on this challenge and identified polycyclic aromatic hydrocarbons (PAHs), such as, benzopyrene, which was shown to be carcinogenic in mouse skin by Cook and his colleagues in 1933. The fact that benzopyrene and many other carcinogens were polyaromatic hydrocarbons lead the Millers (1947) to postulate and verify that many chemical carcinogens required activation to electrophiles (electron seeking moieties) to form covalent adducts with cellular macromolecules. This in turn prompted Conney and the Millers (1956) to identify microsomal enzymes (P450s) that activated many drugs and chemical carcinogens.
