DNA repair, oncogenes and the tumour micro-environment Flashcards
What are most cancers initiated by ?
A change in the DNA sequence of the cell, promoting genetic instability
Name and explain one of these changes ?
1. Chromosomal translocation E.g. -Chronic myelogenous leukaemia (Philadelphia chromosome) resulting from a translocation between the long arms of chromosome 9 and 22 - Burkitt’s lymphoma resulting from a translocation between chromosomes 8 and 14 in B cells
What are some other changes that cause cancers?
- Deletions of chromosomes
e. g. neuroblastoma (loss of chromosome 1)
e. g. retinoblastoma (loss of chromosome 13) - Additional chromosomes
e. g. small lung lymphocytic lymphoma (additional chromosome 12) - Deletion and additions
e. g. acute non-lymphocytic leukaemia (deletion of chromosomes 5 and 7 but additional chromosome 8)
Most agents known to cause cancer cause ?
Genetic change and instability
What are Carcinogenesis (the generation of cancer) linked with ?
Mutagenesis (changes in DNA sequence)
What are some examples of direct chemical carcinogens?
- Dimethylnitrosamine (beer, tyre manufacture)
- Ethylene dibromide (petrol)
- N-nitrosodiethanolamine (cosmetics, lotions, shampoos)
- Polycyclic hydrocarbons (smoke)
- Nitrofurans (food preservatives)
What do some carcinogens have to be activated by ? and give example ?
A metabolic pathway
before they cause mutations by reacting with DNA.
E.g. Aflatoxin and liver cancer
What is the AMES test used to determine ?
The mutagenicity of compounds
What do tumour promoters act synergistically with ?
Carcinogens to promote DNA damage and loss of growth control
How do tumour promoters work on cells?
- Initiator e.g. nitrosodiethanolamine (DNA damage)
- Promoter e.g. phorbol ester (cell proliferation)
Examples of metabolic tumour promoters ?
- Insulin = promotes cancer cell proliferation and decreases apoptosis
- Estrogens = induces cancer cell proliferation
- Oxidative stress - can act as cancer initiator and promoter
- Inflammation - strong association between chronic inflammation and cancer
- IGF-1 = potent growth factor for many cancer lines
Name some Tumour Anti-Promoters ?
- Folic acid (reducing likelihood of DNA damage)
- Antioxidants (preventing oxidative damage and lipid peroxidation, which compound DNA damage in tumour promotion)
- Phytochemicals
- Low-fat plant-based diet
Deletion or alteration of gene on chromosome 5 encodes?
A tumour suppressor gene e.g. Rb allows growth
What does mutation of chromosome 12 result in?
The uncontrolled activation of ras
Deletion or alteration of gene on chromosome 18 allows ?
Reduced contact between cells
Deletion or alteration of gene on chromosome 17 encodes ?
Tumour suppressor e.g. p53
What are some influential factors in human carcinogenesis and explain them ?
- Environment
- In 1775, a high incidence of nasal and scrotum cancer was
noticed in chimney sweeps due to exposure to soot.
- Exposure to UVB radiation and increases the risk of skin cancer
due to formation of pyrimidine dimers in DNA and subsequent
mutations. - Reproductive life
- Nuns are least likely to suffer from cervical cancer, but most
likely to have breast cancer. The former reflects less sexual
activity, the latter relates to the decreased incidence of breast
cancer linked with childbirth.
- Hormonal contraception and fertility treatment also increase the
risk of cancer due to alterations in ovulation schedules. - Diet
- Incidence of specific cancers varies between populations in
different geological locations
How are dietary carcinogens identified ?
By the Ames test
What are some more influential factors in human carcinogens and explain them ?
- Smoking
- The clearest example of a lifestyle factor underlying a specific
cancer. Apart from lung cancer, it is also associated with
pancreas, bladder, kidney, mouth, stomach and liver cancer.
- At least 81 carcinogens identified in cigarette smoke. - Additional influences
- There are risk factors inherent to our physiology
- Aerobic metabolism generates free radicals which are mutagenic
- The process of DNA replication introduces the chances for error
and mutations in the DNA sequence
Women with harmful mutations in either BRCA1 or BRCA2 have a risk of ?
Breast cancer and ovarian cancer
BRCA mutations can also increase risk of ?
Colon, pancreatic and prostate cancers
What are some conventional cancer therapies and explain them ?
- Surgical removal only good for primary site
- Chemotherapy and radiotherapy for metastasised cells.
- These rely on cytostatic effects (prevent proliferation) and cytotoxic effects (promote cell death)
- The aim is to achieve maximum effect on the cancerous cells with minimum side effects
What is the therapeutic index ?
The value between the
minimum effective dose and the maximum tolerated dose (MTD)
What does a higher therapeutic index mean ?
The better the drug (safer)
