Cancer Therapy Overview

Question 1

8 Hallmarks of Cancer

Answer 1

1. stimulate own growth
2. resist inhibitor signals
3. resist programmed cell death
4. multiply indefinitely
5. stimulate growth of blood vessels to supply nutrients to tumors
6. invade local tissue and spread to distant sites
7. abnormal metabolic pathways
8. evade immune system

Question 2

Exogenous DNA damage

Answer 2

carcinogens
UV light
ionizing radiation
viruses

Question 3

Carcinogen pathways

Answer 3

1. base analogs – higher tendency to form tautomers and mismatching
2. chemical modifications – nitrous acid converts adenine to hypoxanthine, this pairs with cytidine not T
3. Intercalation of DNA – flat aromatic rings slip into base pairs and cause insertion/deletions
4. reactive species – form adducts to DNA/modify/mismatch pairing

Question 4

UV light

Answer 4

covalently crosslink adjacent pyrimidine residues –> cause kink in double helix

Question 5

Ionizing radiation

Answer 5

Direct: displaced electron breaks an intact DNA strand

Indirect: displaced electrons/free radicals cause DNA damage

Question 6

Viruses

Answer 6

Integration into host DNA – changes expression patterns of DNA

Question 7

Endogenous DNA damage

Answer 7

Damage from cellular processes

Replication errors

Repair mechanism errors

Question 8

Somatic mutations

Answer 8

acquired mutations in any cell type

passed on via mitosis

Question 9

epigenetic mutations

Answer 9

a type of somatic mutation

alters the control of gene transcription

Question 10

Germline mutation

Answer 10

mutation in germ cell that will be passed to progeny

Question 11

Point mutation

Answer 11

Transition: erroneous base is SAME type [A–>G or C–>T]

Transversion: erroneous base is alternative type [A–>C, T–>G]

Question 12

Nonsense mutations

Answer 12

results in STOP codon

Question 13

Missense mutations

Answer 13

result in alternative codon/different AA sequence

Question 14

Oncogenes

Answer 14

regulate normal cell function

normally OFF–> altered gene results in overexpression or abnormal gene product

Question 15

Tumor Suppressor Gene

Answer 15

regulate and inhibit cell growth & proliferation

genetically altered tumor suppressor genes result in loss-of-expression or expression of non-functional gene

Question 16

Two Hit Hypothesis

Answer 16

BOTH tumor suppressor genes must be mutated– so if inherited one already; ONLY need one additional “hit” compared to two

Question 17

Epigenetic mutations

Answer 17

DNA code intact, but mechanisms/structures that control expression are altered

Question 18

Direct Repair

Answer 18

Alkylation of DNA bases can occur –> O-methylguanine-DNA methyltransferase (MGMT) can reverse

Question 19

Single Strand Break Repair

Base excision & Nucleotide excision

Answer 19

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

Question 20

Double Strand Break Repair

Non-homologous End Joining vs. Homologous Recombination

Answer 20

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