(PM3B) Chemotherapy Flashcards
What is a benefit of combination chemotherapy?
Increased remission
What is a downside of combination chemotherapy?
Increased side effects
What are some potential chemotherapy targets?
(1) Nucleic acids
- DNA double helix
- DNA synthesis
- Amino acid synthesis
(2) Protein targets – enzymes/ receptors/ structural proteins
(3) Other biomacromolecules – cell surface feature (different on cancer cells to normal cells)
What do alkylating drugs do?
Damage DNA
Interfere with cell replication
e.g. procarbazine/ cyclophosphamide
Briefly, what are cytotoxic antibiotics?
Interact with proteins + DNA
e.g. doxorubicin
Briefly, what are antimetabolites?
Incorporated into new nuclear material
Combine irreversibly with vital cellular enzymes
Prevent normal cellular division
e.g. methotrexate/ 5-fluorouracil
Briefly, what are sex hormones and hormone antagonists?
Target biological hormone pathways
Interact with receptor binding sites
e.g. oestrogens/ progesterones
Briefly, what are drugs that affect the immune response?
Include antiproliferative immunosuppressants + immunomodulating drugs
Briefly, what are vinca alkaloids?
Target structural proteins
e.g. vinblastine/ vincristine
Give an example of a chemotherapy drug not classified.
Taxanes
What are alkylating agents?
Highly electrophilic compounds
React with nucleophiles (to form covalent bonds)
- Can react with any nucleophilic group
In DNA: purine bases
- N1 + N3 of adenine
- N3 of cytosine
- N7 in guanine is MOST targeted
Include nitrogen mustards, cisplatin + analogues, mitomycin C
What is the mechanism of action of alkylating drugs?
(1) Drugs with 2 alkylating drugs can bind to guanine on each chain to cross-link the strands
(2) Disrupts replication/ transcription
Can also link 2 guanines on the same chain
- Prevents access by DNA enzymes required for DNA function
What is cyclophosphamide?
Alkylating drug
Prodrug - metabolised in the liver to active form
What is cisplatin?
Alkylating drug
Aggressive treatment
Called CISplatin due to two chlorine are on same side (not diagonal)
What happens to cisplatin in the body?
(1) Enters extracellular environment
(2) Diffuses inside the cell
(3) Chlorine concentration is low inside the cell
(4) Hydrolysis of chlorine (loss)
(5) Replaced with water
(6) Reacts (crosslinks) with DNA at N7 of guanine (nucleophile)
What does cisplatin that actually reacts with the DNA in the cell look like structurally? What processes has it undergone?
Two hydroxyl groups where the chlorine groups were previously
Undergone hydrolysis
How does cisplatin react with DNA?
N7 of guanine acts as a nucleophile
Cisplatin is nucleophile
Kinks DNA if binding 2 guanines on same side
What are cytotoxic antibiotics?
Intercalating agents
Contain a planar aromatic region
Get in between DNA base pairs to inhibit enzymes + distort its structure
e.g. anthracyclines – cardiotoxic side effects
How do cytotoxic antibiotics enter the DNA?
Via the major groove of the double helix
Intercalates using the tricyclic system
Charged amino group attaches to the sugar via an ionic bond to DNA backbone
What is the purpose of intercalation of the DNA by cytotoxic antibiotics?
Inhibition of topoisomerase 2
Which is crucial for effective DNA replication + mitosis
What is etoposide?
Targets topoisomerase 2
NOT via intercalation
Heterocyclic ring system, NOT aromatic
Binds to DNA + protein to keep ends apart – to inhibit re-ligation
What are antimetabolites?
Target enzymes
Structurally resemble the preexisting purines + pyrimidines
Mistaken by the cell for normal metabolites
Can become incorporated into the DNA – do not allow DNA function
- Can cause strand breaks/ premature chain termination
Give an example of a dihydrofolate reductase inhibitor.
Methotrexate
What is the mechanism of action of methotrexate (a dihydrofolate reductase inhibitor)?
Inhibit dihydrofolate reductase
Which is essential for folate metabolism
Slows DNA synthesis + proliferation
What are some side effects of antimetabolites?
(1) Bone marrow suppression
(2) Mucositis
(3) Diarrhoea
Why is folinic acid given with methotrexate for chemotherapy?
Overcomes metabolic block caused by methotrexate
Rescues patient from toxic effect of treatment
Is a tetrahydrofolate so provides an alternative source for the synthesis of nucleic acids
When is methotrexate given in chemotherapy?
Often in combination
To treat neoplastic cancers
Name a thymidylate synthetase inhibitor.
5-fluorouracil
What is a thymidylate synthetase inhibitor?
Allow synthesis of thymidine to be terminated
Stops DNA synthesis
Why is 5-fluorouracil considered a suicide substrate?
Inhibits thymidylate synthetase irreversibly
When is 5-fluorouracil used in chemotherapy?
(1) Breast cancer
(2) Liver cancer
(3) Skin cancer
What are some side effects of 5-fluorouracil?
(1) Neurotoxic side effects
(2) Cardiotoxic side effects
What are antimetabolite DNA polymerase inhibitors?
Prevents DNA polymerase replicating DNA
Can lead to DNA chain termination
Incorporated into DNA strand
e.g. cytarabine
What is cytarabine?
Antimetabolite
DNA polymerase inhibitor
Give an example of an antimetabolite DNA polymerase inhibitor.
Cytarabine
What are the vinca alkaloids?
Inhibit tubulin polymerisation in cell division
e.g. vincristine/ vinblastine/ vindesine
How are vinca alkaloids sourced?
NOT synthesised
Found in plants – adjusted slightly
What are taxanes?
Inhibit tubulin depolymerisation
What is the mechanism of action of taxanes?
(1) Bind to ß subunit of tubulin
(2) Binding accelerates polymerisation + stabilises resultant microtubules
(3) Inhibits depolymerisation because of this
(4) Cell division cycle stopped at G2/M stage
What is a kinase inhibitor?
Target enzymes (structural proteins) – switches off oncogenic signalling
(1) Prevents phosphorylation of signalling proteins
(2) Inactivates signalling proteins
(3) Stops cellular processes
How can cells develop resistance to kinase inhibitors?
Mutation of key amino acids in kinase binding site
What are hormone based therapies?
Used for hormone dependent cancers
Hormone antagonists can be used to block hormone action
e.g. tamoxifen
Why are glucocorticoids used in chemotherapy?
Treatment of leukaemia + lymphoma
Target glucocorticoid receptor signalling
(1) Bind to glucocorticoid receptors
(2) Inhibits cytokine production
(3) Alters oncogene expression
(4) Induces cell cycle arrest + apoptosis
What are monoclonal antibodies?
Cancer cells have individually specific antigens which have been over-expressed
Antibodies that recognise a distinct antigen
What types of monoclonal antibody are there?
(1) Trigger immune response to attack cancer cells, e.g. rituximab
(2) Block signals related to cell division, e.g. trastuzumab
(3) Deliver drugs/ radiation to cancer cells, e.g. ibritumomab
