Targeting cell proliferation and survival Flashcards
Three main hallmarks of cancer ?
Evading TGSs (tumor growth suppressors)
Resisting cell death
Sustaining proliferative signalling
Steps of the Cell Cycle Regulation
All cells must undergo replication!
- Unreplicated DNA
- Spindle assembly (mitosis)
- Chromosome segregation (mitosis)
Chemotherapy action
Works at different stages to stop an overactive cell cycle
- Inhibits cell growth (using growth factor proteins)
- Inhibits DNA duplication (DNA interactive agents)
- Inhibits cell division (Replicative machinery)
Which cytotoxic agents are cell cycle specific ?
Antimetabolites
Vinca alkaloids
Taxanes
Which cytotoxic agents are non-phase specific ?
Anthracyclines
Alkylating agents
Mechanism of action for MTX?
Inhibits dihydrofolate reduction Blocks TMP (trimethoprim) and purine synthesis
Mechanism of action for 5-flouracil? 5FU
Inhibits TMP (trimethoprim) synthesis
Mechanism of action for paclitaxel?
Inhibits seperation of microtubules in anaphase of mitosis
What are Cyclin-dependent Kinase Inhibitors (CDKIs)?
Family of enzymes involved in the cell cycle regulation
Consist of Ser and Thy kinases
Involved in phosphorylation using ATP
CDKIs consist of purine anlalogues that may bind and block the ATP site on the enzyme
Describe action of Palbociclib (Ibrance®) by Pfizer (Approved Nov 2017 by NICE)
- Inhibits CDK4-cyclin binding
(Ineffective against CDK1, CDK2, CDK5) - Effective against ER +ve / HER2 -ve advanced breast cancer in conjunction with hormones
- Median PFS 9.2 months
- DLT (dose limiting toxicities): neutropenia, fatigue, thrombocytopenia
- One cycle £2,950 for pack of 21 capsules (1CAPOD)
What does Azacytidine incorporate into ?
RNA
What does Decitabine incorporate into ?
DNA
What position does DNA methylation occur for epigenetics?
5-position of cytosine by DNA methyltransferases (DNMTs) in CpG islands
- This prevents gene transcription
In relation to epigenetics, what do 5-Azacitidine and 5-aza-2’-deoxycitidine (Decitabine) do?
Restore NORMAL methylation patterns in many haematological malignancies
What is the mechanism for silencing tumour suppressing genees (TSGs)?
Histone deacetylation (HDAC)
E.g. ZOLINZA® (vorinostat) for cutaneous T-cell lymphoma
Define: Telomere
The structure located at the end of the chromosome
They have control over the cell division limit
Cancer cells often have longer telomeres that last through more rounds of DNA replication, allowing for the cells to divide more - Overexpression of telomerase enzyme makes telomeres longer in cancer cella :/
How do we ENABLE REPLICATIVE IMMORTALITY (the 4th Hallmark of cancer)
NB. It means that cancer cells can replicate without limit
Use of telomeres
What do Anti-Mitotic Agents do? Their role.
- Promote microtubule polymerisation
- Inhibit depolymerisation
- Stabilisation of microtubules
and arrests cells in mitosis
What is anti-mitotic agents dependent on to work?
GTP
What is a cyclin dependent kinase inhibitor (CDKI)
Family of enxymes involved in the cell cycle
Involved in phosphorylation using ATP
Ser and Thr kinases
What is the basis for design of cyclin dependent kinase inhibitors?
Purine analogues that might bind and block the ATP site on the enzyme (allowing for space to accommodate further elaboration)
E.g. NU2058
What are telomeres composed of?
Tandem repeats of GC-rich DNA (up to 10kbp in humans)
What is the function/role of telomeres?
Protect chromosome ends from recombination, fusion, or degradation by nuclease
What type of enzyme is Telomerase?
- Type of reverse transcriptase
- Protein-RNA complex that carries the RNA template for synthesising the repeated G-rich telomere
What is the relationship between cancer and telomerase?
Presence of telomerase in cancer cells allows them to maintain telomere length
What do telomeres protect chromosome ends from?
Protect against recombination, fusion and/or degradation by nuclease
What is telomerase enzyme unique for?
Carrying its own RNA template at ALL TIMES (to synthesise G-rich telomeres)
What is the normal level of telomerase and why?
Low levels
Because as telomeres shorten as cells divide
How do we enable replicative immortality? (Hallmark of cancer)
Use of telomeres….
Describe the intrinsic apoptosis pathway
- Triggered in response to DNA damage
- Activated by anticancer therapies via p53
- p53 activates the pathway through protiens of the Bcl-family e.g. BAX, BAK
- BAX causes releases Cytochrome C from mitochondria
- BAX and adaptor APAF1 activates the initiator capsase 9
- Capsase 9 activates capsases 3, 6, 7 causing apoptosis (by destroying critical cell components)
How does p53 activate the intrinsic apoptosis pathway?
Activates it through transcriptional upregulation of pro-apoptotic members of the Bcl-family of proteins e.g. BAX, BAK
Extrinsic vs Intrinsic apoptosis pathway
EXTRINSIC Induces apoptosis INDEPENDENT OF p53 and mitochondria
INTRINSIC induces apoptosis via p53 and uses mitcohondria
Describe the extrinsic apoptosis pathway
- Specific pro-apoptotic ligands e.g. Apo2L/TRIAL activate pro-apoptotic receptors e.g. DR4, DR5
- Activation of receptors by the ligan leads to rapid assembly of Death Inducing Signalling Complex (DISC) & recruitment of initiator capsases 8 + 10 via the Fas-associated death domain (FADD)
- Caspases 8 + 10 activate capsases 3, 6 and 7 which leads to apoptosis
Development of which agents to induce apoptosis? (Two items)
- Inducers of apoptosis
2. Inhibitors of anti-apoptotic proteins
Mechanism of action of Vincristine? (Vinca alkaloid)
Bind to microtubules and inhibit polymerisation to destabilise them… cannot perform metaphase
