Sara Charnecki, Colby College

Date of Award

1995

Document Type

Honors Thesis (Open Access)

Department

Colby College. Chemistry Dept.

Advisor(s)

Julie T. Millard

Abstract

Molecular Basis of Cancer: Cancer, a disease that has had a devastating and frightening impact on current society in the midst of a chemical revolution, represents a class of diseases comprising over 200 known types that affect various regions of the mammalian body (Farmer & Walker, 1985). This disease strikes randomly and is often diagnosed after the disease has progressed beyond present treatment capabilities. Cancer is the result of irregularities in growth, reproduction, and differentiation of cells due to pennanent flaws in genetic information. Mutations caused by environmental factors can be compounded over time to cause carcinomas of different tissues. This disease is often age-related as one mutation alone in the genome IS not likely to cause cancer. The source of the genetic information containing all instruction for cell growth, reproduction, and differentiation is found within every cell's complement of genes in a macromolecule called deoxyribonucleic acid (DNA). To begin to understand this complicated disease and to characterize its mode of action, answers must be sought at the molecular level of DNA. According to Prescott & Flexer (1982), cancers are abnormally growing cells that form malignant tumors that can metastasize or spread through the circulatory system. A system of proto-oncogenes and tumor repressor genes in an animal's genome produce protein products that act either as activators or inhibitors of the mitotic cell cycle for regulation of the rate of cell division. When these specific genes are mutated or altered during retroviral infection, or due to other causes specified below, the equilibrium of the cell cycle is disrupted and uncontrolled cell division can occur, producing tumors that may be malignant and metastasize. Cancers cause death in four major ways. In 25% of cases, the growing tumor interferes with the function of essential organs such as the lungs, liver, brain, or kidneys. In 10% of cases, patients die from severe emaciation, in seven percent hemorrhaging occurs, and in 50% of cancer cases death results from bacterial infection caused by a weakened immune system of the host (Prescott & Flexer, 1982). Modes of Cancer Formation: One known mode of carcinogenicity IS through inheritance. Germinal cells mutate and pass on the abnormality through organismal generations instead of somatic cellular generations In the tissues. The other mode of induced carcinogenicity IS through spontaneous, irreparable changes from environmental agents. Many of the known human cancers are caused by environmental factors where several chemicals or chemical mixtures cause cancer in humans as a result of occupational, medicinal, and societal exposure (Farmer & Walker, 1985). In the last quarter of the nineteenth century, development of skin cancers was documented in workers of tar and shale oil industries, in cotton mill workers exposed to crude lubricating oils used in spinning machines. Cases of bladder cancer in workers in German aniline dye factories were attributed to exposure to aromatic amines (Farmer & Walker, 1985). The first cancers were identified by Percival Potts 10 chimney sweeps in the 19th century (Farmer & Walker, 1985). Non-ionizing (UV light) and ionizing radiation (X-rays) also induce mutations and breaks in genetic material. One example is the tautomerization of nucleotides when radiation changes keto forms of guanine and thymine to enol forms and amino forms of adenine and cytosine to imino forms causing mispairing of the bases and point mutations upon replication (Griffiths et al., 1993). Chemical Carcinogenesis: Carcinogens are efficient inducers of permanent genetic changes such as point mutations, deletions and chromosomal aberrations that inhibit DNA replication and synthesis in vivo and cause abnormalities in the functioning and growth of a cell. If not electrophilic themselves, chemical carcinogens are converted into forms that are highly electrophilic and bind covalently to nucleophilic sites of cellular information macromolecules such as DNA. RNA, or protein (Farmer & Walker, 1985). The most reactive nucleophilic sites in DNA tend to be purine nitrogens, but oxygen and sulfur atoms can also act as binding sites on cellular macromolecules. For example, one known mutagen, 5bromo-uracil, which is highly reactive can replace thymine (5methyl-uracil) and tautornerize spontaneously. Diepoxide compounds, the focus of this study, cross-link DNA by covalently binding N7 guanines across complementary strands (Lawley & Brookes, 1967).

Keywords

DNA, Proteins -- Crosslinking

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