Download Carcinogenesis1

Environmental Health
Carcinogenesis
Week 7
Genotoxicity: toxic effects on
genetic material
• Cancer
• Developmental
(gestational timing crucial)
• Somatic diseases
The nature of “life information”…
• DNA structure
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Base-sugar-triphosphate
Purines: A, G; Pyrimidines: C, T(U)
Double helix; A-T; C-G pairs
Chromosomes (with chromatin)
Humans: 23 autos. pairs + sex pair (XY, XX)
• DNA (code) --> protein: 3nucleic acids /1 aminoacid
• Universal code - the same principles and
molecules in every organism (amoebas to humans)
• Genes (units of information) are the same in every
cell of an organism, but expression of genes varies
by cell/tissue
• Conserved and variable regions of code
Types of Genotoxic effects
• Chromosomal aberrations
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Deletions
Duplications
Inversions
Translocations
Sister chromatid exchanges
• Gene mutations
– Point mutations (base replacement)
– Frameshift mutations
(insertion/deletion of part of gene)
Mutagens:
agents that cause a mutation
• Mutation: Alteration in the genetic code
(DNA sequence of nucleotides), that may
result in altered population of cells or
organisms (nucleic DNA most important)
• Mutations
– Adaptation/survival and speciation
– Disease and death
Effects of mutations
• Silent - no effect
• Change in gene expression
– protein amount, location, timing
• Change in structure of protein
– Single aminoacid change (especially hydrophilic-phobic)
– Multiple aminoacids/Trancation
– Change or loss of activity
• Inefficient or improper biochemical process
• Altered cell function
• Disease; cancer; birth defects; hereditary diseases
Genotoxic factors
• UV light (200-300nm) (>10-10m)
– Thymine dimerization (T-T)
– Cytosine hydration (C + H2O)
• Ionizing radiation
(x/  -rays, <10-10m; ,  particles)
– Single strand, double strand breaks, base
changes
• Biotoxins (aflatoxin-B1)
• Viruses (HPV)
More genotoxic factors
• Chemicals
– Alkylating (diethylnitrosamine)
• Mispairing (G-T vs G-C)
• Depurination (transition, transversion)
• Backbone break
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Arylating (forming DNA adducts)
Intercalating (planar aromatic hydrocarbons)
Base analogues (5-Br-uracil; 5-F-uracil)
Metaphase blockers
Deamination agents
Enzyme inhibitors
Metals (As, Be, Cd, Cr(IV, V), Ni, Pb)
Types of
DNA damage
Reactive oxygen species
Post genetic-damage events
• Repair
• Apoptosis
• Permanent change
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Cell level
Tissue level
Organism level
Species level
See also p. 64 and 262 of Casarett and Doull’s “Toxicology”
Extensive DNA repair system
Cancer, a.k.a. malignant neoplasm
• Uncontrolled growth and spread of abnormal cells
– Solid tumors: liver, lung, intestine, breast, etc
– Blood and lymphatic system, incl. bone marrow
• Reasons for increased cancer incidence:
– increased age
– increased number of carcinogens present
– other?
Cancer is the leading disease-related
cause of years of life lost in the US.
• Causes of Death
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All causes
Unintentional injuries
Cancer
Heart disease
Suicide, homicide
Congenital anomalies
• Years of Life Lost*
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11,761,000
2,306,000
1,803,000
1,563,000
1,247,000
584,000
* Estimated years of life lost before the age of 65
Carcinogenesis Terms
• Chemical Carcinogenesis is the
chemically-induced generation of cancerous
growths in living organisms. Cancerous
growths are often called neoplasms.
• A neoplasm is an abnormal tissue mass, the
growth of which exceeds and is
uncoordinated with that of normal tissue
and persists in a similar manner following
cessation of stimulus. Unique feature is the
continuous replication of a cell population.
Cancer is therefore the
malignant uncontrolled
proliferation of neoplastic cells.
Also a description of a
multitude of different disease
states (~200)
Malignant vs. Benign Neoplasms
• Benign
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Usually encapsulated
Usually non-invasive
Highly differentiated
Rare mitoses
Slow growth
Little or no anaplasia
No metastases
• Malignant
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Encapsulated
Invasive
Poorly differentiated
Mitoses relatively common
Rapid growth
Anaplastic to varying degrees
Metastases
The many faces of cancer
Malignant neoplasms are usually called
carcinomas (endo- or ectoderm) or sarcomas
(mesoderm). Exceptions are hematopoietic
malignancies, melanoma, neuroblastoma, thymoma.
Carcinogens
Genotoxic
Non-genotoxic
Many different
chemical structures
are carcinogenic
Natural/endogenous
molecules with
carcinogenic
properties
Synthetic hormone-like structures
Millers showed that metabolic activation
is key to carcinogenicity (1950’s)
…metabolic activation, continued
Activation can occur also following Phase II reactions
Reactive metabolites bind covalently to DNA
and form adducts which can generate mutations
…adducts, continued
…adducts, continued
Effective elimination of carcinogens is a means of protection
Carcinogenesis
• Initiation
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Dose related
Dividing cells in site are targets
Genetic damage on expressed genes
Can be repaired
• Promotion
– Activation of initiated cell
– First cell of tumor
• Progression
– Rapid (relatively) expansion of abnormal cells
See also p. 267, 271, 275 of Casarett and Doull’s “Toxicology”
Initiation and promotion
Polyaromatic
hydrocarbons
(PAHs) are
initiating agents
in tumor
development
Tumor promoters
TPA is the experimental
skin tumor promoter
found in croton oil
Liver tumor incidence after daily
doses of 2-acetylaminofluorene
Tumor response on mice initiated with 0.2mol
of dimethylbenzanthracene and promoted with
12-O-tetradecanoylphorbol-13-acetate
Potency of carcinogens
• Defined as the slope of the dose-response
curve for induction of neoplasms
• Iball index (% animals with tumors)
• TD50 (used in comparative list)
• T25 (dose rate that gives 25% of neoplasms at specific site)
See also p. 301 of Casarett and Doull’s “Toxicology”
Clonal Selection Model
of Neoplastic Progression
The multistep pathway to colorectal cancer
By B. Vogelstein