• an agent whose administration to previously untreated animals leads to a statistically significant
• increased incidence of malignant neoplasms as compared with that in appropriate untreated control animals
• three classes: chemicals, radiant energy, viruses (not proven to cause cancer in humans)

• importance:
• continued exposure to naturally occurring chemicals is associated with increased cancer incidence
• 100-1000 new chemicals are manufactured each year; not thoroughly tested; potential carcinogens
• cancer drugs may themselves be carcinogenic (i.e. nitrogen mustards: direct acting carcinogens)
• chemical carcinogenesis in the lab gives insight to how cancer starts Þ insight into prevention
• history:
• 1761, Hill: nasal polyps linked to prolonged snuff use
• 1775, Pott: scrotal cancer in former chimney sweeps; incidence declined with daily bathing
• 1915, Japan: cancer induced in rats through prolonged skin exposure to coal tar
• conclusions: environment influences carcinogenesis; prolonged exposure important; carcinogens are not species specific
• examples (these are all pro-carcinogens - need metabolic activation):
• polycyclic hydrocarbons: 1,2,3,4-dibenzathracene; 1,2,5,6-dibenzathracene; 3-methylchloranthrene;
• benzo[a]pyrene; dimethylbenz[a]anthracene
• azo dyes: o-aminoazotoluene; DAB (dimethylaminoazobenzene)_- ‘butter yellow’
• 2-napthylamine: metabolized in liver by conjugation with glucuronic acid and excreted in urine; urinary
• enzyme glucuronidase splits the conjugate into an active carcinogen Þ bladder cancer
• humans are among few species with glucuronidase
• dimethylnitrosamine
• aflotoxin B₁: produced by mold Asperigillus flavus; associated with hepatitis B and liver cancer
• mechanisms:
• carcinogens are not species specific but are organ specific
• result of need for metabolic activation of pro-carcinogen
• different organs contain different enzymes and therefore can activate different carcinogens
• most (or all) chemical carcinogens are electrophilic; combine with nucleophiles (DNA; RNA; N, S, O in proteins)
• interaction of the carcinogen with DNA is only one of the steps necessary to produce cancer – series of events leads to cancer
• latency: extended period of time between initial contact with carcinogen and appearance of cancer (usually years)
• initiation: permanent; alone: no tumor; cells unidentifiable; metabolic activation; sensitive to stage of cell cycle; electrophilic compounds
• promotion: reversible (during early phases); alone: no tumor; phenotypic change in cells; no metabolic activation; modulated by environment; induction of cell proliferation
• complete carcinogens: capable of both initiation and promotion
• incomplete carcinogens: only capable of initiation
• promoters: do not act directly with DNA; diverse structures; diverse effects on cell; most induce cell proliferation
• best studied: TPA (a phorbol ester) Þ activates phospholipase C Þ triggers cell growth
• other human cancer promoters: saccharin, cyclamates; hormones (prostate, breast); fat (colon); alcohol
• cigarette smoke: contains both initiators and promoters
• carcinogen causes the initiation step and promotion leads to clonal expansion and proliferation of the initiated cells

• UV Rays: UVA (320-400nm); UVB (280-320) - current big player; UVC (200-280) - currently ozone filtered
• Ionizing Radiaiton: x-rays; gamma rays; alpha, beta particles; neutrons
• atomic bomb survivors in Japan Þ leukemias in about 7 years; breast, thyroid, lung, colon: later
• DNA repair defects: if can’t repair DNA Þ greater risk for cancer
• xeroderma pigmentosum: sunlight Þ skin cancer
• ataxia-telangiectasia: susceptible to ionizing radiation
• Fanconi’s anemia: susceptible to x-linking agents
• Bloom’s syndrome: susceptible to a variety of DNA damage

Viral Carcinogens – suspected in humans, proven in animals

• Human Paploma Virus (HPV): associated with cervical cancer; mutations in viral genes E6, E7 Þ cancer
• E6 gene Þ breakdown of p53 Þ promotion of mutations
• E7 gene Þ deactivation of tumor supressor pRb
• Epstain Barr Virus (EBV): linked to nasopharyngeal cancer in China
• infects and imortalizes B-cells in immunosuppressed patients Þ lymphomas
• Hepatitis B Virus (HBV)
• Human T-cell leukemia (HTLV-1)