[A] 1.72 Carcinogenesis (chemical and physical agents) Flashcards
Carcinogenesis/oncogenesis: Overview
- Origin is a non-lethal genetic change in the cell
- Neoplastic transformation → Inheritance by daughter cells
- Genetic damage in tissue stem cells (→ Immortalise)
- Monoclonal tumour cells can mutate further (Genetic heterogeneity)
It is hypothesised in carcinogenesis/oncogenesis that…
The mutation of a cell is in the background
- The tumour is monoclonal
Give the steps of carcinogenesis
- Initiation
- Promotion
- Progression
- Malignant cell population develops
Carcinogenesis: Initiation phase
- Mutation of a single cell
- Proliferation ability increases
Carcinogenesis: Promotion phase
- Reversible effects on cells
- Rapid growth
Carcinogenesis: Progression phase
- Initiated cell becomes malignant
- Increased proliferation
Proper carcinogen
Able to induce all the steps of carcinogenesis
Incomplete carcinogen
Initiator
- Can trigger only the initiation phase of carcinogenesis
Natural promotional effects initiating carcinogenesis
- Oestrogen (Endometrial & mammary gland tumours)
- Mediators of chronic inflammation (NFκB signal pathway)
DNA mutation during carcinogenesis can be either…
- Somatic / Germinal
- Spontaneous / Induced
DNA damage can be induced by…
- Chemical agents
- Radiation/physical agents
- Microbial agents
Chemical carcinogens
Approximately 10 million exist
2 mechanisms:
- Direct carcinogens
- Without metabolic transformation
- E.g Chemotherapeutic agents
- Indirect carcinogens
Indirect carcinogenic agents can be caused by…
- Metabolic transformation
- Polycyclic carbohydrates
- Aromatic amines
- Plant & microbial metabolites
Indirect carcinogenic cause: Metabolic transformation
- Individual difference in the activity of CYP450
- Individual sensitivity to chemical carcinogens
- Carcinogenesis in dose and exposition time-dependent
- Accumulation of small doses
Indirect carcinogenic agent: Polycyclic carbohydrates
- Fossil fuels
- Benzoprien: Tobacco burn, cooked animal fat, smoked meat
- Epoxides: Covalent bond to DNA, RNA & proteins
- Smoke & Tar
Indirect carcinogenic agent: Aromatic amines
β-naphthol amines: Paint industry (bladder tumours)
Indirect carcinogenic agent: Plant & microbial metabolites
Aflatoxin: Aspergillus flavus B1
(Hepatocellular carcinoma)
Indirect carcinogenic agent: Other miscellaneous
- Vinyl-chloride: Coolant
- Hormones
- Asbestos
- Arsenic, nickel, chromium
- Insecticides, fungicides, Biphenyl
- Food preservatives
Indirect carcinogenic agents: Mechanism of action
- Damage to oncogens
- Damage to tumor suppressor genes (E.g P53)
What can increase the effect of indirect carcinogenic agents?
Promotors
- Hormones
- Phenols
- Some drugs
Acting against the DNA-repair mechanisms
Radiation & physical agents causing carcinogenesis
- UV light
- Radiation
- Nuclear fission
- Ionising radiation
UV light as a cause of carcinogenesis
- Melanoma - Intermittent, intensive exposure (sunbathing)
- Basal cell & squamous cell carcinoma - Cumulative
- Squamous cell carcinoma in animals
Nuclear fission as a cause of carcinogenesis
Radionucleotides
- Miners of radioactive elements - 10x more likely to get lung cancer
- Hiroshima/Nagasaki atomic bomb/Chernobyl
- Myeloid leukaemia
- Thyroid gland carcinoma
- Mammary gland carcinoma
- Colonic carcinoma
- Lung carcinoma
Ionising radiation as a cause of carcinogenesis
E.g X-rays
- Chromosome fragmentation
- Translocation
- Mutatuon
UV rays as a cause of carcinogenesis
Nucleotide excision repair damage → Pirimidine dimers
Can induce further mutations
