Chemotherapy chemistry MOA Flashcards
What are the 8 classes of cytotoxic drugs
- Drugs acting directly on nucleic acid
- drugs acting on enzymes: antimetabolites
- hormone-based therapies
- drugs acting on structural proteins
- inhibition of signalling pathway
- Miscellaneous enzyme inhibitors
- Antibodies, antibody conjugates and gene therapy
- Miscellaneous
What are the different stages of a cell cycle
G1 - growth phase
S - DNA synthesis
G2 - growth and preparation for mitosis
M - mitosis - cell division
What drugs target the different stages of the cell cycle
G1 - hormonal agents and antineoplatic enzymes
S - Anti-metabolites targets and terminate DNA strand elongation
G2 - Groove binding and Topoisomerase I and II inhibitors
M
- Vinca Alkaloid & Colchine - destabilise the microtubules
Taxanes - stabilised the microtubules
What drugs act directly on nucleic acids
- Alkylating agents
- Intercalating agents
- Non-intercalating topoisomerase ‘poisons’
- Groove binding
- O6 - methylation of Guanine
- Organoplatinum complexes
What drugs act directly on enzymes
Antimetabolites e.g
- Pyrimindine antagonists
- Purine antagonist
- Folate antagonist
What drugs act on structural protein
Microtubules targeting drugs
- Microtubules DESTABILISNG agent
- Microtubules STABILISNG agent
What drugs are DNA repair enzymes inhibitor
-PARP inhibitors
What are examples of protein kinase inhibitors
- Tyrosine kinase inhibitor
- EGFR inhibitors
What drugs are hormone-based (endocrine) therapies
- Selective Estrogen receptor mudolators (SERM)
- Aromatase inhibitors
- Leutenising Hormone-release Hormone agonist (LHRHa)
- Anti-androgens
What is an example of an ALKYLATING AGENT and what is the MOA
-CYCLOPHOSPHAMIDE
MOA:
-Alkylating agents form a highly reactive aziridinium ion that can be attacked by nucleophilic DNA
bases such as guanine.
- In this reaction, alkyl groups are transferred to the nucleophilic sites of DNA
bases. This can occur twice leading to cross-linked DNA.
-The damage caused cannot be repaired
meaning cancer cells can no longer proliferate.
What are the limitation of alkylating agents
-they can’t differentiate between healthy and cancer cells
having a straight chain alkyl group leads to:
-a fast reaction
-so there’s no tissue specificity
-and more side-effects/toxicity
So water or any other nucleophile could inactivate the mustard
having an aromatic group e.g benzene rings leads to:
- stabilised lone pair on N due to resonance
- enhanced tissue selectivity
- decreased aziridinium ion formed
- lower side-effects
What is the resistance mechanism for Alkylating agents
- cancer cells pump drugs out before it has a chance to have an effect
- the cancer cells can increase the amount of pumps it has to be able to pump the drug out
- it can also develop ‘agent specific’ DNA repair processes
What is an example of an INTERCALATING AGENT and what is the MOA
Thalidomide
MOA:
- they must have planar aromatic rings
- they insert themselves into the space between successive DNA base pairs
- which can lead to slight unwinding of the DNA helix
- which alters the DNA structure thus causing cell death
What is the importance of Topoisomerase enzyme
-plays key role in DNA replication, transcription, chromosome separation and DNA repair
What is an example of a NON-INTERCALATING TOPOISOMERASE INHIBITOR and the MOA
-ETOPOSIDE
MOA:
- stabilise covalent intermediate between DNA and topoisomerase II
- So DNA strands are no rejoined
- This has a cytotoxic effect
-shows selectivity for cancer cells
What is an example of an ANTHRACYCLINE and the MOA
-DOXORUBICIN
MOA:
- DNA intercalation
- Topoisomerase II ‘poison’
CARDIOTOXIC
What is an example of a GROOVE BINDING and the MOA
-BLEOMYCIN
MOA:
- Binds to the major groove of DNA
- Has a high affinity of DNA
How does Bleomycin resistance occurs
-Bleomycin hydrate converts Bleomycin to an inactive (carboxylate) ionised metabolite so Bleomycin can no longer anchor itself to DNA groove
What is an example of a O6- methylation of Guanine and the MOA
-PROCARBAZINE
MOA:
- adds a methyl group to O6 position on Guanine
- Means methylguanine pairs with thymine instead of cytosine
- which is a ‘mispairs’
- this leads to point mutation and cell destruction.
What is an example of an ORGANOPLATINUM COMPLEX and the MOA
-CARBOPLATIN, CISPLATIN, OXALIPLATIN
MOA:
- Organoplatinum complex
- contains electron-deficient metal atom which attracts electron rich DNA nucleophiles
- It is displaced by water before reacting with DNA electron donating ligand
- It is bi-functional so it can accept two DNA nucleophiles
- leads to interstrand or intrastrand crosslinks
- the DNA is distorted and unable to be repaired
- leads to cell cycle arrest
- then apoptosis
How is CARBOPLATIN, CISPLATIN, OXALIPLATIN excreted and what is their dose based on
- excreted by the kidney
- dose is based on renal function
How do ANTIMETABOLITES work
- they are ‘false’ substrate for critical nucleotide biosynthesis enzymes
- so they block the synthesis of DNA nucleotides and reduce tumour growth
What’s an example of a PYRIMIDINE ANTAGONIST and what is the MOA
- 5-fluorouricil and CAPCITABINE
- they mimic dUMP to prevent synthesis of dTMP
- so no product is formed and no co-factor released.
- thymidylate synthase (TS) is NOT regenerated
- so no thymine is synthesised
- so apoptosis occurs because DNA cannot be made
What’s an example of a PURINE ANTAGONIST and what is the MOA
-THIOGUANINE & MERCAPTOPURINE
MOA:
-prevents synthesis of adenine and guanine
