Lecture 26: Cancer Chemotherapy Flashcards
What is the leading cause of death in Canada?
Cancer
What is cancer characterized by?
Abnormal cell growth with potential to spread to other parts of the body (metastasis)
What is Cancer caused by?
Environmental and genetic factors
What is Radon?
A naturally occuring gas that occurs in the environment the causes lung cancer
How can cancer be associated with viral infections?
- HIV with hodgkin’s and non-hodgkin’s lymphoma
* HPV with cervical cancer
What are the characteristics of genes associated with cancer?
They are low penetrating genes, meaning the mutations only slightly increase risk but not substantially. But some are high penetrance like BRCA 1
When does cancer arise?
When genes that regulate cell growth are mutated
What happens in a normal cell if there is a mistake in duplicating the genetic material?
Either its fixed or the cell undergoes apoptosis
What are the 5 phases in the cell cycle?
- GI phase
- S phase
- G2 phase
- M phase
- G0 phase
What is the GI phase?
A checkpoint to ensure cell ready for DNA synthesis
What is the S phase?
DNA synthesis
What is the G2 phase?
Checkpoint to ensure cell is ready for mitosis
What is the M phase?
Mitotic phase (cell divided)
What is the G0 phase?
The Quiescent state
What are the two groups of genes important in the regulation of the cell cycle?
- Tumor suppressor genes
* Oncogenes
What is the longest part of the cell cycle?
G1
What is the shortest part of the cell cycle?
M
What do Tumor suppressor genes do?
Repress the cell cycle or promote apoptosis
What three ways do tumor suppressor gene repress the cell cycle or promote apoptosis?
- Inhibit cell division
- Initiate apoptosis following irreversible DNA damage
- DNA repair proteins (BRCA) can repair
What happens if there is a mutation in the tumor suppressor genes?
Then they cannot suppress cell division
What is p53?
A tumor suppressor protein that regulates the cell cycle
What are the characteristics of p53 in tumors?
It is mutated in 50% of all tumors
What are Proto-oncogenes?
Normal genes involved in cell growth and proliferation or inhibition of apoptosis
What can mutations in oncogenes do?
Increase expression causing increase cell growth and proliferation
what are the two types of mutations?
- Point mutations
* Chromosomal translocation
What are point mutations?
Small scale deletion or insertions which affect its expression
What is chromosomal translocation?
When two separate chromosomal regions become abnormally fused
What is Philadelphia chromosome?
A specific genetic abnormality in chromosome 22 found in leukemia cancer cells (abnormal translocation of chromosome 9 and 22)
What gene does the fusion in the Philadelphia chromosome create?
A new gene BCR-ABL
What does the BCR-ABL gene lead to?
Unregulated expression of protein tyrosine kinase activity leading to unregulated cell cycle and cell division
What acts in concert to cause cancer?
Usually multiple oncogenes and mutated tumor suppressor genes
What is 1/3 of cancer treated with?
Local treatment strategies such as surgery or radiotherapy
What approach for cancer treatment is required when metastasis is present?
A systemic approach
What percentage of cancer drugs cure all cancer patients when the tumor is diagnosed at advanced stage?
10%
What do anti-cancer drugs do?
Interfere with cell cycle
When are anti-cancer drugs more effective?
When cancer is detected early or when used with other treatments
Which phases in the cell cycle do anti-cancer drugs usually work at?
The S and M phase
Why are tumor cells more susceptible to S and M phase anti-cancer drugs?
Because they generally have a higher percentage of proliferating cells than normal cells
What cells are susceptible to damage from cytotoxic drugs?
Normal tissues that proliferate rapidly (bone marrow, hair follicle, intestinal epithelium)
What do Pyrimidine analogues do?
Compete with normal pyrimidine precursors for the enzyme thymidylate synthase (TS)
What do Pyrimidine analogues compete with normal pyrimidines for?
The enzyme Thymidylate Synthase (TS)
What is TS required for?
The conversion of dUMP to dTMP
What kind of drug is 5-fluorouracil (5-FU)?
A pyrimidine analogue and a prodrug
How does 5-FU work?
It looks like dUMP and competes for the active site of thymidylate synthase
What is the active form of 5-FU?
FdUMP
How is 5-FU activated?
In the liver with metabolism
What kind of drug is 6-mercaptopurine?
A purine analogue
How does 6-mercaptopurine work?
It inhibits purine nucleotide biosynthesis and metabolism by inhibiting an enzyme called PRPP amidotransferase
What enzyme does 6-mercaptopurine inhibit?
PRPP amidotransferase
What does PRPP amidotranferase do?
Takes the ribose sugar and converts it into an intermediate base pair called IMP that can be converted into GMP or AMP
What is the rate limiting factor for purine synthesis?
The work of the enzyme PRPP amidotransferase
What are Alkylating agents?
Highly reactive compounds which covalently link chemical groups found in nucleic acids
What do Alkylating agents lead to?
Cross linking between strands of DNA and strand breakage
What is particularly susceptible to the formation of covalent bonds with alkylating agents?
N7 atom of guanine
When are cancer cells most susceptible to Alkylating Agents?
In the late G1 and S phases
What drug is an Alkylating agent?
Cisplatin
What kind of drug is Cisplatin?
An alkylating agent
What is Folic acid converted into?
FH4 cofactors
What do FH4 cofactors provide?
Methyl groups for the synthesis of precursors of DNA
What do FH4 cofactors provide?
Methyl groups for the synthesis of precursors of DNA
What do Folic Acid Analouges do?
Interfere with FH4 metabolism thereby inhibiting DNA replication
What kind of drug is Methotrexate?
An anti-folate
How does Methotrexate work?
Binds with high affinity to the active catalytic site of dihydrofolate reductase which inhibits production of FH4 cofactors
During what stage of the cell cycle is Methotrexate effective?
During the S phase
What drug is an anti-folate?
Methotrexate
What are Natural Products?
Compounds extracted from plants or bacteria with anti-cancer properties
What are the Natural Products?
- Vinca Alkaloids
- Taxanes
- Epipodophyllotoxins
- Camptothecins
What are Vinca Alkaloids derived from?
The periwinkle plant
What do Vinca Alkaloids do?
They inhibit tubulin polymerization which disrupts the assembly of microtubules involved in mitotic spindle apparatus (M phase)
Which Phase do Vinca alkaloids act on?
The M phase
What are Taxanes derived from?
The Pacific yew tree
How do Taxanes work?
They promote microtubule assembly through high affinity binding which inhibits mitosis and cell division by preventing them from being dismantled
Which phase do Taxanes work on?
The M phase
What is an example of a Taxane?
Paclitaxel
What kind of drug is Paclitaxel?
A taxane
What are Camptothecins derived from?
Camptotheca acuminata
What are DNA topoisomerases?
Nuclear enzymes that reduce torsional stress in supercoiled DNA through strand breakage and resealing
What do Camptothecins do?
They bind and stabilize the normally transient DNA-topoisomerase I complex and inhibits the religation of DNA causing single stranded breaks in DNA
What phase do Camptothecins affect?
The S-phase
What is an antibiotic cancer drug?
Anthracycline
What type of drug is Anthracycline?
An anti-cancer drug
What are the four mechanisms of actions of Anthracycline?
- Inhibit topoisomerases
- Generate free radicals (DNA mutagenesis)
- High affinity binding to DNA
- Bind cellular membrane to alter fluidity and ion transport
What do Tyrosine Kinase Inhibitors do?
Inhibit tyrosine kinase domain of the BCR-ABL oncoproteins
What are Tyrosine Kinase inhibitors used to treat?
Leukemia
How do Epidermal Growth factor inhibitors work?
They inhibit cell growth and proliferation
What is Cetuximab?
A monoclonal antibody directed against the extracellular domain of EGFR
What do Selective estrogen receptor antagonists do?
Blocks binding of estrogen to estrogen sensitive cancer cells in breast tissue
What is a selective estrogen receptor antagonist?
Tamoxifen
What is Primary resistance?
Spontaneous resistance in the absence of prior exposure to anti-cancer drugs so tumor was never susceptible to drugs
What is acquired resistance?
Develops in response to anticancer drug
