Carcinogenesis Flashcards
What is the main feature?
Structurally diverse but majority are electrophilic and interact spontaneously with biological nucleophiles e.g proteins and DNA
What two mechanisms allow metabolism of carcinogens?
Oxidation by cytochrome p450
Conjugation to a hydrophilic substance e.g glucoronate - often inadvertently generates reactive unstable intermediates such as epoxides.
How does carcinogen induced and virus induced transformation differ?
C - mutate proto-oncogenes
V - introduce activated oncogene.
What can carcinogens be?
Stimulators of proliferation (Na saccharin)
Mutagens (carcinogen adducts found bound to DNA)
What is a short term method for detecting carcinogens?
Ames mutation test
Homogenise liver
Mix test + homogenate
Liver enzymes activate test compound
Add salmonella (which can’t grow in his absence)
Count mutated colonies (can grow without added his).
What evidence suggests that activation is an early step in carcinogenesis?
PCR shows activating ras mutation within 12 days of carcinogen treatment (months before cancer develops).
Mouse skin carcinogenesis with dimethylbensanyhracene - ras mutation found pre-malignant papilloma before full progression to malignancy.
How does the 3T3 cell line provide evidence that cooperation is required ?
Partially transformed so instead transfect isolated primary fibroblasts;
Ras - morphologically transforms primary cells but soon die.
Myc, PyT, E1A - alone - immortalised cell lines at high f but look normal.
Ras + Myc - transformation.
What kind of initiation and promotion are needed to cause tumours?
What is significant concerning promotion?
Single low dose of carcinogen (initiator)
Then REPEATED exposure to promoter (substance which on own never caused tumours.
NON-MUTAGENIC.
What is TPA and how does it function?
A promoter (non mutagenic)
Active component of croton oil
Substitutes for DAG and more stable so activates PKC.
Fibroblasts ( pkc stimulation by TPA proliferation )
Keratinocytes ( premature terminal differentiation)
