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CHEMICAL CARCINOGENESIS

Properties of Chemical Carcinogenesis:
1
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, may cause about 70-90% of
cancer
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The idea that environmental exposure to chemicals might cause cancer
has a long history since the 18th century beginning with John Hill
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Since then, many other substances have been identified as carcinogens
as a result of occupational exposure, such as tars, soot’s, oils, asbestos
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Carcinogens are structurally diverse – there are no common elements
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Some carcinogens act directly:
• Intrinsically electrophilic
• Cause tumours at or near immediate site of administration (i
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site
of subcutaneous injection)
6
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7
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9
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10
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g
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11
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g
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• Experimentally, lag duration is inversely proportional to doseincreased carcinogen shortens delay
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12
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However,
generally, you need repeated applications over long periods of time
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There are multiple independent steps (“genetic hits”) produces a tumour
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Single, low dose of carcinogen – too low to be effective on its own à
Initiator
2
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The order is very important because:
• Promoter before initiator gives no tumours
• Initiator alone gives no tumours
• Can separate exposure to initiator and promoter by a long interval
and still get tumours à the initiation is a stable state
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These are events that encourage selective amplification of the initiated
cells are reversible
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Their mechanisms include:
• Chronic inflammation
• Enhance proliferation (e
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wound healing, hormones)
- Cell growth increases the chances of further mutations
- Epigenetics (activation or suppression of gene expression)

3
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It’s active in
croton oil (a common promoter) and activates protein kinase C (PKC)
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Belongs to a family of ser/thr protein kinases and there are at least 10
isotopes known
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The conventional isotopes are calcium phospholipid and diacyl glycerol
(DAG) dependent
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DAG is produced during receptor-mediated stimulation of PI turnover
(via phospholipase C)
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DAG also lowers the calcium requirement for enzyme activity
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TPA substitutes for DAG and is more stable, causing a down-regulation of
PKC
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In fibroblasts, stimulation of PKC by TPA causes proliferation, however, in
keratinocytes, TPA causes premature terminal differentiation
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After metabolic activation, ultimate carcinogens are mostly electrophiles
capable of reacting with many cellular components, including protein and
nucleic acids
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It is commonly believed that the most critical interaction is with DNA
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Evidence supported this is:
• Cancer cell phenotype is inherited cell to cell, suggesting that
there is in fact some somatic mutation
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Consistent with the
irreversible nature of initiation and the persistence of initiated
cells
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• Many carcinogens are also mutagens
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It is also possible that carcinogens acts as stimulators for proliferation
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This has been found in long-term rodent carcinogenicity tests, where the
agent used frequently at its maximum tolerated dose causes:
• Stimulation of cell division to repair the damage
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Carcinogens can be detected using a “lifetime rodent bioassay”,
whereby there is chronic exposure to the test substance for
approximately two years and usually at high levels
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However, this is difficult in humans because it is unethical
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8
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• A rat liver homogenate is prepared to produce a metabolically
active extract
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• The homogenate and bacterial strain are combined with a
suspected mutagenic substance
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Tumour Oncogenes:
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2
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3
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• Next, isolate the DNA from the foci, transfect the normal cells and
you will continue to get the foci
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• To identify the genes, you extract the focal DNA and inserted it into
a phage
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• Usually, these are often the same oncogenes already encountered
in retroviruses such as H-ras and myc
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Carcinogens seem to be targeting the same genes that human cancer cells
target
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Normal genes contain copies of these proto-oncogenes but do not
generate foci in transfection assays
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This means that tumour-derived genes must be altered in some way
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A classic example is in the bladder carcinoma where a single base change
(Gly to Val) in codon 12 of H-ras, causing the proto-oncogene to become
an oncogene
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Carcinogen treatment of DNA in vitro can produce the same mutation in
ras
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Using very sensitive techniques (involving PCR), activating ras mutations
have been found within 12 days of carcinogen treatment – this is months
prior to over cancer develops
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In mouse skin carcinogenesis with dimethylybenzanthracene, ras
mutations have been found in the pre-malignant papillomas before
progression to full malignancy
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This demonstrates that oncogene activation is an early event in
carcinogenesis
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Transformation of cells by acute retrovirus or by activated oncogenes
from tumour cells in vitro, might suggest that only a single genetic
change is required to generate a tumour
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However, there is a long lag period between carcinogen treatment and
tumour development
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Epidemiology suggests that multiple changes are needed
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Tumour progression argues for multiple changes – tumours start benign
and get progressively more malignant with time
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Viruses could transform the cells in a single step due to their horizontal
spread from cell to cell through infection
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Activated ras fails to transform normal, freshly isolated primary
fibroblasts and require co-transfection with another oncogene
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This indicates that there are two oncogene classes with different modes
of action – they need co-operation between oncogenes to generate a
tumour
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However, it is important to note that two activated oncogenes are not
sufficient, thereby, there need to be additional changes, i
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tumour
suppressor gene loss such as p53 or Rb

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