Biological Basis of Cancer Therapy Flashcards by Georgia Leggett

What are the 5 most common cancers worldwide?

Lung 
Breast 
Bowel 
Prostate  
Stomach

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What are the 4 main anti-cancer modalities?

Radiotherapy
Chemotherapy
Surgery
Immunotherapy

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List 6 different types of cytotoxic chemotherapy.

Alkylating agents  
Pseudoalkylating agents  
Antimetabolites 
Anthracyclines  
Vinca alkaloids + taxanes 
Topoisomerase inhibitors

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What are the main types of targeted therapy for cancer?

Monoclonal antibodies

Small molecule inhibitors

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What is the term used to describe chemotherapy that is given:
Pre and post surgery

Pre: Neoadjuvant
Post: Adjuvant

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How do alkylating agents work?

Add an alkyl groups to the guanine residues in DNA
Causes cross-linking of DNA strands + prevents DNA from uncoiling at replication
This triggers apoptosis (via a DNA checkpoint pathway)
It encourages mis-pairing

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What class of anti cancer drugs includes the following:
Chlorambucil 
Cyclophosphamide 
Dacarbazine 
Temozolomide

Alkylating agents.

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How do pseudoalkylating agents work?

Have the same mechanism as alkylating agents but use platinum instead of alkyl groups

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What class of anti cancer drugs includes the following:
Carboplatin
Cisplatin
Oxaliplatin

Pseudoalkylating agents.

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List 9 side effects of alkylating and pseudoalkylating agents

Alopecia (except carboplatin)  
Nephrotoxicity 
Neurotoxicity 
Ototoxicity (platins) 
Nausea
Vomiting
Diarrhoea
Immunosuppression
Tiredness

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How do anti-metabolites work?

Masquerade as purine or pyrimidines leading to inhibition of DNA replication + transcription
Leads to DNA double strand breaks + apoptosis
Can also be folate antagonists

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Which class of anticancer drugs includes the following:
Methotrexate  
Capecitabine  
Gemcitabine  
5-fluorouracil 
6-mercaptopurine
Fludarabine

Anti-metabolites.

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State 9 side effects of anti-metabolites.

Alopecia (not 5-fluorouracil or capecitabine) 
Bone marrow suppression 
Increased risk of neutropenic sepsis 
Nausea 
Vomiting
Mucositis
Diarrhoea
Fatigue 
Palmar-plantar erythrodysesthesia (PPE)

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How do anthracyclines work?

Intercalate into DNA/ RNA sequences + inhibit transcription + replication
Also blocks DNA repair
Create DNA + cell membrane damaging oxygen free radicals

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Which class of anti cancer drugs includes the following:
Doxorubicin
Epirubicin

Anthracyclines.

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State 7 side effects of anthracyclines.

Cardiac toxicity (probably due to free radicals) 
Alopecia  
Neutropenia 
Nausea
Vomiting
Fatigue  
Red urine (doxorubicin –‘the red devil’)

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How do vinca alkaloids and taxanes work?

Vinca alkaloids inhibit assembly of microtubules
Taxanes inhibit disassembly of microtubules
This forces cells into mitotic arrest

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State 7 side effects of vinca alkaloids and taxanes

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Nerve damage (peripheral + autonomic neuropathy)
Hair loss
Nausea
Vomiting
Bone marrow suppression
Arthralgia (severe joint pain without swelling or signs of arthritis)
Allergy

How do topoisomerase inhibitors work?

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Topoisomerase= enzymes that unwind DNA + induce temporary single + double strand breaks in the phosphodiester backbone
Topoisomerase inhibitors alter the binding of topoisomerase to DNA + allow permanent DNA breaks

Which class of anti cancer drug includes the following:
Topotecan
Irinotecan
Etoposide

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Topoisomerase inhibitors.

State 6 side effects of topoisomerase inhibitors.

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Irinotecan= acute cholinergic type syndrome (diarrhoea, abdominal cramps, diaphoresis– so given atropine) 
Hair loss  
Nausea
Vomiting
Fatigue  
Bone marrow suppression

What are the 6 hallmarks of cancer?

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SPINAP 
Self-sufficient  
Pro-invasive + metastatic  
Insensitive to anti-growth signals  
Non-senescent
Anti-apoptotic  
Pro-angiogenic

What are the 4 hallmarks of cancer that have recently been added?

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DIE U 
Dysregulated metabolism 
Inflammation 
Evades immune system  
Unstable DNA

Give 3 examples of receptors that are over-expressed in cancer. What is the consequence of this?

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EGFR: over-expressed in many breast + colorectal cancers
HER2: breast
PDGFR: glioma (brain)
Increased kinase cascade + signal amplification

Give an example of a ligand that is over-expressed in some cancers. What is the consequence of this?

VEGF: prostate, kidney + breast cancer | Increased kinase cascade + signal amplification

Give two examples of constitutive (ligand independent) receptor activation in cancer. What is the consequence of this?

EGFR: lung cancer FGFR: head + neck cancers, myeloma Increased kinase cascade + signal amplification

What do each of the following suffixes mean in relation to monoclonal antibodies: a. -momab b. -ximab c. -zumab d. -mumab

–momab: Derived from mouse antibodies –ximab: Chimeric antibody –zumab: Humanised antibody –mumab: Fully human antibody

Describe the structure of humanised monoclonal antibodies.

Murine regions are interspersed within the light + heavy chains of the Fab portion

Describe the structure of chimeric monoclonal antibodies.

Murine component of the variable region of the Fab section is maintained integrally

What effect can monoclonal antibodies have on receptors and their activation?

Target extracellular component of receptors + can prevent receptor dimerization, neutralise the ligand + cause internalisation of the receptor Also activate Fc-receptor-dependent phagocytosis or cytolysis induced complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity (ADCC)

Give two examples of monoclonal antibodies used in oncology.

Bevacizumab: binds + neutralises VEGF Cetuximab: targets EGFR

How do small molecule inhibitors work?

Bind to kinase domain of tyrosine kinase receptors within the cytoplasm + block autophosphorylation + downstream signalling

What was the 1st targeted treatment for cancer and how did it work?

Glivec (imatinib): a small molecule inhibitor that targets the ATP binding region within the kinase domain of BCR-ABL1 This inhibits kinase activity of ABL1

Give four examples of small molecule inhibitors that inhibit receptors.

Erlotinib (EGFR) Gefitinib (EGFR) Lapatinib (EGFR/HER2) Sorafenib (VEGFR)

Give three examples of small molecule inhibitors that inhibit intracellular kinases.

Sorafenib (Raf kinase): in addition to its anti-VEGFR effects Dasatinib (Src kinase) Torcinibs (mTOR inhibitors)

State 6 advantages and 7 disadvantages of monoclonal antibodies.

Advantages: High target specificity Cause ADCC, complement-mediated cytotoxicity + apoptosis induction Can be radiolabelled Cause target receptor internalisation Long half-life (lower dosing frequency) Good for haematological malignancies Disadvantages: Large + complex structure (lower penetration) Less useful against bulky tumours Only useful against targets with extracellular domains Not useful for constitutively activated receptors Cause immunogenicity + allergy IV administration Expensive

State 5 advantages and 2 disadvantages of small molecule inhibitors.

Advantages: Can target tyrosine kinases without an extracellular domain or which are constitutively activated Pleiotropic targets (useful in heterogenic tumours/cross-talk) Oral administration Good tissue penetration Cheap Disadvantages: Shorter half-life, more frequent administration Pleiotropic targets (more unexpected toxicity)

State 4 resistance mechanisms to targeted therapies.

Mutations in ATP binding domain Intrinsic resistance Intragenic mutations Upregulation of downstream signalling/ parallel pathways

Explain how anti-sense oligonucleotides work.

Short, single-stranded DNA-like molecules Bind to complementary sequence on mRNA + hinder its translation Recruits RNase H to cleave the target mRNA

Name a successful B-Raf inhibitor and list 3 side effects

Vemurafenib | Side effects: arthralgia, skin rash + photosensitivity

Explain how the PD-1 receptor-PDL1 ligand system works.

PD-1 receptor on surface of cancer cells When PDL-1 binds to the PD-1 receptor, the body’s T cells can no longer recognise tumours as foreign So blocking the PD-1 receptor will stimulate the immune system

Name a drug that inhibiting PD-1.

Nivolumab (anti-PD1 antibody)

List 6 genetic mutations that can cause cancer

Chromosome translocation Gene amplification Point mutations with promoter/ enhancer regions of genes Deletions/ insertions Epigenetic alterations to gene expression Inherited

What is the target of cytotoxic chemotherapy?

Targets all rapidly dividing cells in the body (inc. gut mucosa + bone marrow cells)

Biological Basis of Cancer Therapy Flashcards

(44 cards)