16 and 17 - Antieoplastic Agents I and II Flashcards
What specific criteria are important for cells to pass the G1/S checkpoint?
- Are cell nutrition, size and environment favorable?
- Is all DNA intact?
If so, the cell will prepare for DNA replication and enter S phase
What specific criteria are important for cells to pass the G21/M checkpoint?
Is DNA completely replicated?
If so, the cell will enter mitosis
What specific criteria are important for cells to pass the metaphase/anaphase checkpoint?
- Is all DNA intact?
- Are all chromosomes attached to the mitotic spindle?
If so, the cell will begin chromatid separation and prepare for cytokinesis
What do tumor suppressor genes do?
- They encode proteins that are important components of checkpoints
- Tumor suppressors can halt the cell cycle and induce apoptosis if ideal conditions are not met
What is the key tumor suppressor?
p53
Cells that become cancerous often have reduced function in this key tumor suppressor
What are oncogenes?
Oncogenes are mutated versions of genes that support normal cellular proliferation (proto-oncogenes)
What are the three mechanisms by which oncogenes form?
1 - Point mutation
2 - Fusion-protein
3 - Proto-oncogene duplication or amplification
Describe how a point mutation can form an oncogene
- A mutation in one of the nucleotides that causes a change in an amino acid in a regulatory region in the protein product of the gene
- An amino acid substitution (called a point mutation) can cause the protein to be hyperactivated or resistant to normal degradative mechanisms that prevent too much expression of the protein
- Hyperactivity or resistance can lead to uncontrolled proliferation
Describe how a fusion-protein can form an oncogene
- A fusion protein is when a chromosomal translocation causes a fusion of two genes
- The fusion-protein can have increased activity
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Give an example of a fusion-protein
Example
- Philadelphia chromosome
- Fusion between chromosomes 9 and 22
- This causes a fusion between the ABL gene and the BCR gene
- The normal protein product of ABL is a tyrosine kinase that promotes cellular growth
- BCR-ABL fusion protein causes a significant increase in the tyrosine kinase activity of ABL
- This leads to uncontrolled proliferation of myeloid cells causing chronic myeloid leukemia (CML
Describe how duplication or amplification can form an oncogene
When a proto-oncogene is duplicated or amplified, it causes the formation of many extra chromosomal copies
What does it mean to say that the killing of cancer cells is “first order”?
It means that chemo drugs kill a constant PERCENTAGE of cancer cells, not a constant number
Give an example of first order killing
If a drug kills 99 % of cells with the first dose, it will not kill the remaining 1% with the second dose (it will only kill 99 % of the remaining cells).
What are the four goals of cancer therapy?
1 - Curative intent
2 - Adjuvant therapy
3 - Neoadjuvant therapy
4 - Palliative care
What is curative intent?
When we begin treating some cancers, we intend to cure them
- Acute lymphocytic leukemia (ALL)
- Testicular cancer
- Acute myelogenous leukemia (AML)
What is adjuvant therapy?
- Drug therapy is given after the primary treatment (typically surgery, but can also be radiation)
- After surgery or radiation there are remaining cancer cells and those are the ones we are trying to treat
- This is done to decrease the chances that the cancer will return
What is neoadjuvant therapy?
- Drug therapy that is done to shrink a tumor before surgical resection
- This can be done to allow a previously unoperable tumor to become operable
What is palliative care?
- Palliative care provides temporary improvement of quality of life by reducing
symptoms. - Therapies with combinations of drugs with different mechanisms of cytotoxicity and different adverse
effects are often administered to maximize cell kill, while minimize side-effects. - This is most often the rule rather
than the exception
How do tumor cells become resistant to chemotherapy treatments?
- Tumor cells often have genetic instability, which allows them to become resistant to chemotherapy
- Gene duplications of the multi-drug resistant (MDR) transporter can cause cell to survive despite chemotherapy
- This is because they are able to pump many different cytotoxic agents out of the cell
- This can enable the tumor cell count to grow despite treatment
What is epithelial-mesenchymal transition (EMT)? How does this induce resistance to chemotherapy?
- The process by which cells lose adhesive properties and become motile
- Changes that occur during EMT cause the cells to become resistant to drugs
What are other ways that resistance can occur?
The tumor is able to…
- Undergo epigenetic changes
- Induce drug efflux
- Repair DNA damage
- Inhibit cell death
- Metastasize via EMT
- Alter the drug
- Inactivate the drug
