Cancer Therapy Overview Flashcards
8 Hallmarks of Cancer
- stimulate own growth
- resist inhibitor signals
- resist programmed cell death
- multiply indefinitely
- stimulate growth of blood vessels to supply nutrients to tumors
- invade local tissue and spread to distant sites
- abnormal metabolic pathways
- evade immune system
Exogenous DNA damage
carcinogens
UV light
ionizing radiation
viruses
Carcinogen pathways
- base analogs – higher tendency to form tautomers and mismatching
- chemical modifications – nitrous acid converts adenine to hypoxanthine, this pairs with cytidine not T
- Intercalation of DNA – flat aromatic rings slip into base pairs and cause insertion/deletions
- reactive species – form adducts to DNA/modify/mismatch pairing
UV light
covalently crosslink adjacent pyrimidine residues –> cause kink in double helix
Ionizing radiation
Direct: displaced electron breaks an intact DNA strand
Indirect: displaced electrons/free radicals cause DNA damage
Viruses
Integration into host DNA – changes expression patterns of DNA
Endogenous DNA damage
Damage from cellular processes
Replication errors
Repair mechanism errors
Somatic mutations
acquired mutations in any cell type
passed on via mitosis
epigenetic mutations
a type of somatic mutation
alters the control of gene transcription
Germline mutation
mutation in germ cell that will be passed to progeny
Point mutation
Transition: erroneous base is SAME type [A–>G or C–>T]
Transversion: erroneous base is alternative type [A–>C, T–>G]
Nonsense mutations
results in STOP codon
Missense mutations
result in alternative codon/different AA sequence
Oncogenes
regulate normal cell function
normally OFF–> altered gene results in overexpression or abnormal gene product
Tumor Suppressor Gene
regulate and inhibit cell growth & proliferation
genetically altered tumor suppressor genes result in loss-of-expression or expression of non-functional gene
Two Hit Hypothesis
BOTH tumor suppressor genes must be mutated– so if inherited one already; ONLY need one additional “hit” compared to two
Epigenetic mutations
DNA code intact, but mechanisms/structures that control expression are altered
Direct Repair
Alkylation of DNA bases can occur –> O-methylguanine-DNA methyltransferase (MGMT) can reverse
Single Strand Break Repair
Base excision & Nucleotide excision
Base excision– DNA glycosylase removed damaged base to create an apurinic/apyrimidinic (AP) site, AP endonuclease cleaves the backbone at the AP site and DNA polymerase/DNA ligase repair the gap
Nucleotide excision– same mechanism but removes 12-24 nucleotides in surrounding DNA
Double Strand Break Repair
Non-homologous End Joining vs. Homologous Recombination
Non-homologous End Joining:
proteins recognize & bind broken DNA –> recruits additional proteins to complex, brings together loose ends and nucleases/polymerases process the ends –> break is repaired but left with error-prone region
Homologous Recombination: proteins recognize and bind broken DNA –> end restriction to single stranded DNA –> single strands repaired and exchanged –> strand annealing repairs double break WITHOUT error-prone region
