12. Biological basis of cancer treatment Flashcards
How is cytotoxic chemotherapy generally administered?
IV
Recall the 6 types of non-targetted cytotoxic chemotherapy available
- Alkylating agents
- Pseudoalkylating agents
- Anthracyclines
- Topoisomerase inhibitors
- Vinca alkaloids and taxanes
- Antimetabolites
Recall the MOA of alkylating agents
Add alkyl groups to guanine residues in DNA, producing cross-linking and therefore preventing DNA unravelling for replication. Triggers apoptosis.
Recall an example of an alkylating agent
Chlorambucil
Recall the MOA of pseudo-alkylating agents
Adds platinum to guanine residues in DNA - this creates cross-links between strands and prevents uncoiling for replication –> apoptosis
Recall an example of a pseudo-alkylating agent
Cisplatin
Recall the 2 classes of antimetabolite cytotoxic chemotherapy
- Purine/pyrimidine analogues
2. Folate antagonists
Recall the MOA of purine/pyrimidine analogues as a cytotoxic chemotherapy
By masquerading as a base they inhibit DNA synthesis - breaks DNA strand –> apoptosis
Recall the MOA of folate antagonists as a cytotoxic chemotherapy
Inhibit dihydrofolate reductase, thus preventing nucleic acid production
Recall an example of an anti-folate drug
Methotrexate
Recall the MOA of anthracyclines as a cytotoxic chemotherapy
Intercalate between bases in DNA, producing free radicals and therefore causing damage to DNA and cell membrane
Recall an example of an anthracycline drug
Doxorubicin
Recall the MOA of vinca alkaloids as a cytotoxic chemotherapy
Inhibition of assembly of mitotic spindle
Recall the MOA of taxanes as a cytotoxic chemotherapy
Inhibition of disassembly of mitotic spindle
What is the normal function of topoisomerase?
DNA uncoiling: induces temporary strand breaks in the phosphodiester backbone to protect free ends of DNA from aberrant recombination events
Recall the MOA of topoisomerase inhibitors as a cytotoxic chemotherapy
They alter the binding of the topoisomerase complex to make breaks in phosphodiester backbone permanent
Recall 3 possible mechanisms of resistance to chemotherapy
- DNA-repair mechanisms upregulated
- PARP excises faulty bases
- Cell effluxes cell via ABC transporters (ATP-binding cassette)
Recall 2 classes of targeted chemotherapy
- Small molecule inhibitors
2. Monoclonal antibodies
What type of malignancy are monoclonal antibody-based chemotherapies particularly effective against?
Blood malignancies
Recall 3 advantages of small-molecule inhibitors as a chemotherapy
- Cheap
- Oral administration
- Can target TKs with no EC domain
Recall 3 useful comparisons of the usefulness of monoclonal antibodies vs small molecule inhibitors
- Half life: much longer for Monoclonals
- Ability to target TKs without EC domains: only SMIs
- Cost: SMIs much cheaper
Recall a disadvantage of monoclonal antibodies as a chemotherapy
Low penetration due to their bulky structure
Recall a disadvantage of small molecule inhibitors as a chemotherapy
Unexpected toxicity due to pleiotropic targets
Recall the MOA of small molecule inhibitors
They bind to the intracellular kinase of RPTKs leading to blockade of autophosphorylation and therefore downstream signalling
Give an example of a small molecule inhibitor and its MOA
Glivec
Binds the ATP-binding region of the kinase domain of ABL1 - used to treat Philadelphia chromosome CML
Recall the MOA of monoclonal antibodies as a chemotherapy
Bind the extracellualar domain of RPTKs, preventing dimerisation and leading to receptor endocytosis
Recall a monoclonal antibody used in colorectal cancer
Bevacizumab - targets VEGF
Recall 3 possible mechanisms of resistance to targeted chemotherapies
- Heterogeneity of tumour
- Mutation in ATP-binding region of RPTK
- Upregulation of a different proliferation pathway to divide despite drug
Recall 2 genome-related chemotherapy options
- RNA interference
2. Anti-sense oligonucleotides
What are anti-sense oligonucleotide therapies particularly useful for?
“undruggable” targets
Recall 4 side effects that are common to most cytotoxic chemotherapies
- Alopecia
- Bone marrow suppression
- Fatigue
- Nausea and vomiting
In which tissues are alkylating agents particularly toxic?
Kidneys, mouth, neurons
In which tissues are anthracyclines particularly toxic?
Cardiac
In which tissues are vinca alkaloids and taxanesparticularly toxic?
Nerves
Recall 3 new therapeutic avenues being explored for cancer therapy
- Nanotherapy for cytotoxic drug delivery
- Immunotherapies
- Targeting cancer metabolism
