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Stage 4 Content > Chemotherapy chemistry MOA > Flashcards

Chemotherapy chemistry MOA Flashcards

1
Q

What are the 8 classes of cytotoxic drugs

A
  1. Drugs acting directly on nucleic acid
  2. drugs acting on enzymes: antimetabolites
  3. hormone-based therapies
  4. drugs acting on structural proteins
  5. inhibition of signalling pathway
  6. Miscellaneous enzyme inhibitors
  7. Antibodies, antibody conjugates and gene therapy
  8. Miscellaneous
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2
Q

What are the different stages of a cell cycle

A

G1 - growth phase

S - DNA synthesis

G2 - growth and preparation for mitosis

M - mitosis - cell division

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3
Q

What drugs target the different stages of the cell cycle

A

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

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4
Q

What drugs act directly on nucleic acids

A
  • Alkylating agents
  • Intercalating agents
  • Non-intercalating topoisomerase ‘poisons’
  • Groove binding
  • O6 - methylation of Guanine
  • Organoplatinum complexes
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5
Q

What drugs act directly on enzymes

A

Antimetabolites e.g

  • Pyrimindine antagonists
  • Purine antagonist
  • Folate antagonist
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6
Q

What drugs act on structural protein

A

Microtubules targeting drugs

  • Microtubules DESTABILISNG agent
  • Microtubules STABILISNG agent
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7
Q

What drugs are DNA repair enzymes inhibitor

A

-PARP inhibitors

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8
Q

What are examples of protein kinase inhibitors

A
  • Tyrosine kinase inhibitor

- EGFR inhibitors

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9
Q

What drugs are hormone-based (endocrine) therapies

A
  • Selective Estrogen receptor mudolators (SERM)
  • Aromatase inhibitors
  • Leutenising Hormone-release Hormone agonist (LHRHa)
  • Anti-androgens
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10
Q

What is an example of an ALKYLATING AGENT and what is the MOA

A

-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.

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11
Q

What are the limitation of alkylating agents

A

-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
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12
Q

What is the resistance mechanism for Alkylating agents

A
  • 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
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13
Q

What is an example of an INTERCALATING AGENT and what is the MOA

A

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
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14
Q

What is the importance of Topoisomerase enzyme

A

-plays key role in DNA replication, transcription, chromosome separation and DNA repair

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15
Q

What is an example of a NON-INTERCALATING TOPOISOMERASE INHIBITOR and the MOA

A

-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

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16
Q

What is an example of an ANTHRACYCLINE and the MOA

A

-DOXORUBICIN

MOA:

  • DNA intercalation
  • Topoisomerase II ‘poison’

CARDIOTOXIC

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17
Q

What is an example of a GROOVE BINDING and the MOA

A

-BLEOMYCIN

MOA:

  • Binds to the major groove of DNA
  • Has a high affinity of DNA
18
Q

How does Bleomycin resistance occurs

A

-Bleomycin hydrate converts Bleomycin to an inactive (carboxylate) ionised metabolite so Bleomycin can no longer anchor itself to DNA groove

19
Q

What is an example of a O6- methylation of Guanine and the MOA

A

-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.
20
Q

What is an example of an ORGANOPLATINUM COMPLEX and the MOA

A

-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
21
Q

How is CARBOPLATIN, CISPLATIN, OXALIPLATIN excreted and what is their dose based on

A
  • excreted by the kidney

- dose is based on renal function

22
Q

How do ANTIMETABOLITES work

A
  • they are ‘false’ substrate for critical nucleotide biosynthesis enzymes
  • so they block the synthesis of DNA nucleotides and reduce tumour growth
23
Q

What’s an example of a PYRIMIDINE ANTAGONIST and what is the MOA

A
  • 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
24
Q

What’s an example of a PURINE ANTAGONIST and what is the MOA

A

-THIOGUANINE & MERCAPTOPURINE

MOA:
-prevents synthesis of adenine and guanine

25
Q

What’s an example of a FOLATE ANTAGONIST and what is the MOA

A

-METHOTREXATE

MOA:

  • competitive inhibitor for dihydrofolate reductase (DHFR) enzyme
  • this halts the synthesis of dTMP
  • so thymine not produces
  • leads to cell death
26
Q

What’s an example of a microtubules DESTABILISING agent and what is the MOA

A

VINCA ALKOLID, COLCHINE

MOA:
-block tubular polymerisation by binding at the interface of 2 tubulin heterodimer

  • and inhibits the uptake of GTP
  • this is essential for microtubule elongation
  • so it means mitotic spindles cannot be formed
  • this prevents the cell from undergoing mitosis
  • so overall effect the cell cannot replicate
27
Q

What’s an example of a microtubules STABILISING agent and what is the MOA

A

TAXANES e.g Paclitaxel

MOA:
-they promote microtubule polymerisation

  • stabilising of microtubule means mitotic spindle doesnt break down
  • so cells are arrested in mitosis
  • overall effect - cells are unable to replicate
28
Q

What’s an example of a SERM and what is the MOA

A

-TAMOXIFEN

MOA:

  • competitively binds to oestrogen receptor
  • so it prevents oestrogen from binding
  • slows down cell proliferation driven by oestrogen
  • it is a cytostatic drug
29
Q

What’s an example of a AROMATASE INHIBITOR and what is the MOA

A

-LETROZOLE

MOA:

  • Binds to aromatase enzyme
  • so prevents conversion of androgens to oestrogen
  • this prevents tumour growth
30
Q

Why is ENZALUTIMIDE (anti-androgen) such as effective drug for prostate cancer

A
  • oral drug
  • that inhibits multiple steps in androgen receptor signalling pathway
  • inhibits binding of androgens to androgen receptors
  • inhibits translocation of androgen receptor to the nucleus
  • inhibits associated of androgen receptor to the DNA
31
Q

What is DNA-PK (DNA- protein kinase)

A

Enzyme that plays key role in the non-homologus end-joining pathway of DNA double-strand break repair

32
Q

Why is DNA-PK (DNA- protein kinase) inhibitors effective

A

-Giving patients DNA-PK inhibitors in combo w/ other anticancer agents enhances the effects of that agent because DNA-PK inhibitors prevents the repair of the damage caused leading to cell death.

33
Q

What is PARP

A

a DNA-repair enzyme involved in DNA base-exicison repair pathway

34
Q

What is an example of PARP inhibitors

A
  • Niraparib
  • Rucaparib
  • Daparib
35
Q

Why are PARP inhibitors effective

A

Inhibiting PARP enzymes would result in cell death because damage to the DNA would not be repaired so cell death occurs

36
Q

What are Protein Kinase and why are they important in cancer therapy

A
  • protein kinase are involved in many signalling processes
  • the genes coding for protein kinases are often mutated in cancer cells
  • competitive inhibitors of protein kinases can inhibit signalling pathways that no longer functional and prevent uncontrolled proliferation of cells
  • Each kinase has unique ATP binding domain that can be targeted for example EGFR
37
Q

What are examples of EGFR inhibitors and their MOA

A
  • Erlotinib
  • Gefitinib

bind reversibly to ATP binding site on EGFR to prevent signalling cascade to inhibit cell proliferation

38
Q

What is the side effect of Taxanes

A
  • peripheral neuropathy
  • myelosuppression
  • skin reactions
  • arthralgia
39
Q

What is the side effect of Vincristine

A
  • Nausea
  • Vomiting
  • Weight loss
  • mouth sores
  • diarrhoea
40
Q

What are the side effects of Bortezomib

A
  • Peripheral Neuropathy
  • Fatigue
  • nausea and vomiting
41
Q

What is the side effects of Thiladomide

A 
•take at night cos can cause dizziness/drowsiness
•teratogenic 
•peripheral neuropathy
-constipation
-venous thromboembolism

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