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A. General Pharmacology > 7. Anti-Cancer Drugs > Flashcards

7. Anti-Cancer Drugs Flashcards

1
Q

Classification of anticancer agents

A

Cytotoxic drugs:

  1. alkylating agents
  2. platinum based drugs
  3. anti-metabolites
  4. microtubules inhibitors
  5. cytotoxic antibiotics
  6. topoisomerase inhibitors

PACMAT

Platinum based drugs, Alkylating agents and Cytotoxic antibiotics → phase non-specific

Targeted therapy:

  1. Tyrosine kinase inhibitors
  2. Receptor tyrosine kinase inhibitors
  3. Immunotherapy: therapeutic antibodies, T-cell immunotherapy
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2
Q

Mechanism of cytotoxic drugs

A
  1. Greatest selectivity against proliferating cells
  2. By interrupting cellular process e.g. DNA replication, microtubule formation, which are crucial for cell division
  3. Functions through inducing apoptosis
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3
Q

How do cytotoxic drugs reduce cancer load

A

Via log-kill hypothesis

  • follows first order kinetics → a fixed percentage of tumour cells per cycle
  • one-log drug kills 90%, two-log drug kills 99%, three-log drug kills 99.9%
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4
Q

Advantages of chemotherapy combinations

A
  1. Maximal cell kill within range of toxicity for each drug
  2. Provides synergy between drugs in heterogenous tumour cell populations
  3. Prevent or slow development of drug resistance
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5
Q

Common chemotherapy side effects

A

Common acute toxicity:

  • myelosuppression
  • nausea, vomiting, gastrointestinal effects
  • mucous membrane ulcerations
  • alopecia

Late organ toxicity:

  • cardiotoxicity
  • pulmonary toxicity
  • nephrotoxicity
  • neurotoxicity
  • haematological and immunologic impairment
  • secondary malignancies
  • teratogenicity
  • endocrine disruption
  • premature menopause, infertility
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6
Q

MOA of alkylating agents

A
  1. Phase non-specific
  2. Reactive alkyl group predominately forms covalent bonds with DNA, cross linking DNA
  3. Disrupts DNA replication and transcription
  4. Causes double and single-strand DNA breaks
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7
Q

Examples of alkylating agents

A
  1. nitrogen mustard: cyclophosphamide, chlorambucil
  2. nitrosoureas: carmustine, lomustine, semustine
  3. alkyl sulfonates: busulfan
  4. ethylenimines: thiotepa
  5. triazenes: dacarbazine, procarbazine
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8
Q

MOA of platinum analogue

A
  1. Phase non-specific
  2. DNA adducts leads to intra-strand crosslinks, less so interstrand crosslinks, DNA-protein crosslinks
  3. Broad spectrum activity: in combination therapy cures testicular cancer
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9
Q

Examples of platinum analogue

A

cisplatin, carboplatin, oxaliplatin

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10
Q

Adverse effects of platinum analogue

A

Acute: nausea and vomiting (cisplatin)
Delayed: myelosuppression, nephrotoxicity, peripheral sensory neuropathy (cisplatin and oxaliplatin)

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11
Q

MOA of anti-metabolites

A
  1. Cell cycle-specific
  2. Interfere with 1 or more enzymes or reactions necessary for nucleic acid synthesis
  3. Restrict the flow of precursors for DNA replication
  4. Also some incorporated into DNA and produce stress signals
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12
Q

Examples of anti-metabolites

A
  1. Methotrexate: inhibits dihydrofolate reductase

2. 5-Fluorouracil: inhibits thymidylate synthase (TS)

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13
Q

MOA of cytotoxic antibiotics

A
  1. Phase non-specific
  2. Inhibits DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing DNA replication
  3. Creates iron-mediated free oxygen radicals that damage the DNA and cell membranes
  4. Inhibition of Topoisomerase II
  5. Alter membrane fluidity and ion transport
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14
Q

Examples of cytotoxic antibiotics

A
  1. Anthracyclines: doxorubicin, daunorubicin, idarubicin, epirubicin
  2. Others: Mitomycin C, bleomycin
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15
Q

Adverse effects of anthracyclines

A
  1. Cardiac toxicity
  2. Local toxicity
  3. Nausea, vomiting, alopecia
  4. Myelosuppressive: dose limiting toxicity
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16
Q

Examples of microtubule inhibitors

A
  1. Vinca alkaloids: vinblastine, vincristine, vinorelbine

2. Taxanes: paclitaxel, docetaxel, cabazitaxel

17
Q

MOA of microtubule inhibitors

A
  1. Microtubule inhibitors bind to the beta subunit of tubulin
  2. Vinblastine and related drugs bind to the polymerising end, preventing elongation of the microtubule
  3. Paclitaxel stabilises the microtubule, preventing shortening or depolymerisation
18
Q

Toxicities of microtubule inhibitors

A
  1. Hypersensitivity
  2. Myelosuppression
  3. Peripheral neuropathy
  4. Myalgia
  5. Bradycardia (e.g. taxol)
19
Q

MOA of topoisomerase inhibitors

A

Inhibition of type I or type II topoisomerase interferes with transcription and replication of DNA by disruption of appropriate DNA supercoiling

20
Q

Examples of topoisomerase inhibitors

A

Type I topoisomerase inhibitors: irinotecan, topotecan

Type II topoisomerase inhibitors: etoposide, teniposide

21
Q

Toxicities topoisomerase inhibitors

A
  1. nausea, vomiting, diarrhoea (irinotecan)
  2. myelosuppression
  3. alopaecia (etoposide)
22
Q

Example of tyrosine kinase inhibitors

A

Imatinib (Gleevec): used in treatment against Ph+ CML
- BCR-ABL Tyrosine Kinase inhibitors

Erlotinib and Gefitinib: used in treatment against NSCLC
- EGFR tyrosine kinase inhibitors

Alectinib: used in treatment against NSCLC
- ALK tyrosine kinase inhibitors

23
Q

Types of immunotherapy used in cancer

A
  1. Therapeutic antibodies
    - neutralising
    - antibody-dependent cellular cytotoxicity/ complement-dependent cytotoxicity
    - antibody-drug conjugate
  2. T-cell immunotherapy
    - Adoptive cell transfer (ACT): engineering patient’s own immune cells to target and kill cancer cells
    - Chimeric Antigen Receptor (CAR) T-cells: T cells are engineered to express CARs that recognise tumour cells
    - Immune checkpoint inhibitors: CTLA-4 and PD-1
24
Q

Current challenges in cancer-drug resistance

A

Intrinsic:

  1. Tumour type and factors: heterogeneity, mutations, genotypes
  2. Site: drugs may not cross BBB to reach tumour in the brain → intrathecal injection into spinal canal
  3. Size: necrotic core, poor vascularisation, diminished growth fraction

Acquired:
Selection of resistant clones → over expression of ABC Transport Proteins
- membrane transport proteins that use ATP to actively efflux toxins and other substances out of the cells
- major mechanism of resistance against anthracyclines

A. General Pharmacology (7 decks)

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