Biological Basis of Cancer Therapy Flashcards
What are the 5 most common cancers worldwide?
Lung Breast Bowel Prostate Stomach
What are the 4 main anti-cancer modalities?
Radiotherapy
Chemotherapy
Surgery
Immunotherapy
List 6 different types of cytotoxic chemotherapy.
Alkylating agents Pseudoalkylating agents Antimetabolites Anthracyclines Vinca alkaloids + taxanes Topoisomerase inhibitors
What are the main types of targeted therapy for cancer?
Monoclonal antibodies
Small molecule inhibitors
What is the term used to describe chemotherapy that is given:
Pre and post surgery
Pre: Neoadjuvant
Post: Adjuvant
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
What class of anti cancer drugs includes the following: Chlorambucil Cyclophosphamide Dacarbazine Temozolomide
Alkylating agents.
How do pseudoalkylating agents work?
Have the same mechanism as alkylating agents but use platinum instead of alkyl groups
What class of anti cancer drugs includes the following:
Carboplatin
Cisplatin
Oxaliplatin
Pseudoalkylating agents.
List 9 side effects of alkylating and pseudoalkylating agents
Alopecia (except carboplatin) Nephrotoxicity Neurotoxicity Ototoxicity (platins) Nausea Vomiting Diarrhoea Immunosuppression Tiredness
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
Which class of anticancer drugs includes the following: Methotrexate Capecitabine Gemcitabine 5-fluorouracil 6-mercaptopurine Fludarabine
Anti-metabolites.
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)
How do anthracyclines work?
Intercalate into DNA/ RNA sequences + inhibit transcription + replication
Also blocks DNA repair
Create DNA + cell membrane damaging oxygen free radicals
Which class of anti cancer drugs includes the following:
Doxorubicin
Epirubicin
Anthracyclines.
State 7 side effects of anthracyclines.
Cardiac toxicity (probably due to free radicals) Alopecia Neutropenia Nausea Vomiting Fatigue Red urine (doxorubicin –‘the red devil’)
How do vinca alkaloids and taxanes work?
Vinca alkaloids inhibit assembly of microtubules
Taxanes inhibit disassembly of microtubules
This forces cells into mitotic arrest
State 7 side effects of vinca alkaloids and taxanes
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?
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
Topoisomerase inhibitors.
State 6 side effects of topoisomerase inhibitors.
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?
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?
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?
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)
