clinical oncology 1: cancer treatment Flashcards
what are the main anti-cancer treatment modalities?
surgery
radiotherapy
chemotherapy
immunotherapy
what are the types of genetic mutations that can cause cancer?
- chromosome translocation
- gene amplification (copy number variation)
- point mutations within promoter or enhancer regions of genes
- deletions / insertions
- epigenetic alterations to gene expression
- inherited
what are the types of systemic cancer therapies?
cytotoxic chemotherapy
targeted therapies
what are some types of cytotoxic chemotherapies used?
- alkylating agents
- antimetabolites
- anthracyclines
- vinca alkaloids & taxanes
- topoisomerase inhibitors
what are the types of targeted therapies?
small molecule inhibitors
monoclonal antibodies
how do cytotoxic chemotherapies work?
select’ rapidly dividing cells by targeting their structures (mostly DNA except taxanes affect microtubules)
how & when is cytotoxic chemotherapy given?
IV or orally
can be given:
- adjuvant (post-op)
- neoadjuvant (pre-op)
- as monotherapy or in combination
- with curative or palliative intent
what are the side effectes of cytotoxic chemotherapy and why do they arise?
- hair loss
- mucositis
- immunnosuppression
- nausea & vomiting
- diarrhoea
- nephrotixicity
- neurotoxicity
- tiredness
- systemic effects mean all rapidly dividing cells in body are affected
how do alkylating agents work?
- add alkyl groups to guanine residues in DNA
- cross-link DNA strands and prevents DNA from uncoiling at replication
- trigger apoptosis (via checkpoint pathway)
- encourage mis-pairing (oncogenic)
what are some examples of alkylating agents?
chlorambucil
cyclophosphamide
decarbazine
temozolomide
how do pseudo-alkylating agents work?
add platinum to guanine residues in DNA
- same mechanism of cell death as alkylating agents
what are some examples of pseudo-alkylating agents?
carboplatin
cisplatin
oxaliplatin
(basically anything with platin in the name)
how do anti-metabolites work?
masquerade as purine / pyrimidine residues -> inhibition of DNA synthesis, DNA double strand breakage, apoptosis
what are some examples of anti-metabolites?
- methotrexate (folate)
- 6-mercaptopurine
- decarbazine
- fludarabine
- 5-fluorouracil
- capecitabine
- gemcitabine
what are the side effects of anti-metabolites?
- hair loss
- bone marrow suppresion -> anaemia & thrombocytopenia
- increased risk or neutropenic sepsis
- nausea, vomiting
- mucositis & diarrhoea
- palmar-plantar erythrodysesthesia
- fatigue
how do anthracyclines work?
inhibit transcription & replication by intercalating nucleotides within the DNA/RNA strand
- also block DNA repair (mutagenic)
- create DNA and damagine free oxygen radicals
what are some examples of anthracyclines?
- doxorubicin
- epirubicin
what are the side effects of anthracyclines?
- cardiax toxicity
- alopecia
- neutropenia
- nausea & vomiting
- fatigue
- skin changes
- red urine
how do vinca alkaloids & taxanes work?
inhibit assembly (VA) or disassembly (taxanes) or mitotic microtubules -> dividing cells undergo mitotic arrest
what are some side effects of vinca alkaloids & taxanes?
- nerve damage (peripheral neuropathy, autonomic neuropathy)
- hair loss
- nausea & vomiting
- bone marrow suppression
- arthralgia
- allergy
how do topoisomerase inhibitors work?
topoisomerases regulate torsional strain within DNA during replication & transcription by inducing temporary breaks in phosphodiester backbone of DNA -> specific topoisomerase inhibitors alter binding of complex to DNA -> DNA breaks permanently
wha are some examples of topoisomerase inhibitors?
- topotecan & irinotecan (topo I)
- etoposide (topo II)
what are some side effects of topoisomerase inhibitors?
- acute cholinergic type syndrome (diarrhoea, abdominal cramps, diaphoresis - managed with atropine)
- hair loss
- nausea & vomiting
- fatigue
- bone marrow suppression
what are some mechanisms for cell resistance to cancer drugs?
DNA repair mechanisms upregulated & increased dna damage repair -> less likely for dna double strand to break
- DNA adducts replaced by base excision pair
- drug effluxed from the cell by ATP-binding cassette (ABC) transporters
what are the pros and cons of dual kinase inhibitors?
reduce chance of alternate pathways continuing when one pathway is blocked
- however increased toxicity
what are the 10 hallmarks of the cancer cell?
- self-sufficient
- insensitive to anti-growth signals
- anti-apoptotic
- pro-invasive and metastatic
- pro-angiogenic
- non-senescent
- disregulated metabolism
- evades immune system
- unstable dna
- inflammation
how are normal cells stimulated to grow?
growth signals transmitted into cell via growth factors binding transmembrane receptors -> activates downstream signalling pathways
how can signal amplification be increased in cancer cells?
- overexpressoin of receptors (HER2, EGFR)
- overexpression of ligand (eg VEGF in prostate, kidney + breast)
- ligand independent receptor activation (eg EGFR (lung), FGFR (head+neck))
how can receptors on cancer cells be targeted?
monoclonal antibodies
what do the suffixes of monoclonal antibodies mean?
momab = derived from mouse
ximab = chimeric (murine component of variable region of fab is maintained integrally)
zumab = humanised (murine regions interspersed within light + heavy chains of fab portion)
mumab = fully human
how do monoclonal antibodies work?
neutralise ligand -> receptor doesn’t dimerise -> no downstream signalling
- target extracellular component of receptor
- cause internalisation of receptor
- complement-dependent cytotoxicity -> immune response
what are some examples of monoclonal antibodies used in oncology?
bevacizumab (binds and neutralises VEGF) - improves survival in colorectal cancer)
cetuximab (targets EGFR)
what do small molecule inhibitors do?
bind to kinase domain of tyrosine kinase within the cytoplasm -> blocks autophosphorylation & downstream signalling
what is glivec?
small molecule inhibitor that targets ATP binding region within kinase domain
what are some examples of SMIs inhibiting receptors?
erlotinib
gefitinib
lapatinib
sorafinib
what are some examples of SMIs inhibiting intracellular kinases?
sorafinib, dasatinib
what are some advantages of MABs?
- high target specificity
- cause ADCC, complement mediated cytotoxicity + induce apoptosis
- can be radiolabelled
- cause target receptor internalisation
- long half-life
- liked by regulatory authorities
what are some disadvantages of MABs?
- large with complex structure -> low tumour / BBB penetration
- less useful against bulky tumours
- only work against targets with extracellular domains
- cause immunogenicity, allergy
- parenteral administration
- expensive
what are some advantages of SMIs?
- can target TKs without extracellular domain / which are ligand activated
- oral administration
- good tissue penetration
- cheap
what are some disadvantages of SMIs?
- short half-life -> more frequent administration
- more unexpected toxicity
what are some resistance mechanisms to targeted therapies?
- mutations in ATP binding domain
- intrinsic resistance
- intragenic mutations
- upregulation of downstream / parallel pathways
what are anti-sense oligonucleotides?
single-stranded chemically modified DNA-like molecule
- complementary nucleic acid hybridisation to target gene hinders translation of specific mRNA
- good for ‘undruggable targets’
what is RNA interference?
single stranded complementary RNA
what is nivolumab?
anti PD-1 antibody - big success in treatment of melanoma
what are some examples of new ways that cancer treatment can be delivered?
- nanotherapies
- virtual screening technologies
- immunotherapies using antigen presenting cells to present ‘artificial antigens’
- targeting cancer metabolism
