Cancer 9: Biological basis of cancer therapy Flashcards
(34 cards)
What are 4 Main anti-cancer treatment types ?
- Surgery
- Radiotherapy
- Chemotherapy
- Immunotherapy
Systemic therapy:
- cytotoxic chemotherapy
- -> alkylating agents
- -> antimetabolites
- -> anthracyclines
- -> Vinca alkaloids and taxanes
- -> Topoisomerase inhibitors
- targeted therapies
Small molecule inhibitors
Monoclonal antibodies
How does cytotoxic chemotherapy work?
- administrated IV / Oral
- Cytotoxics target rapidly dividing cells by targeting their structures
- Alkylating agents, Antimetabolites, Anthracyclines, Topoisomerase inhibitors target DNA
- Taxanes + Vinca alkaloids target microtubules
What are alkylating agents?
How do they work?
- Add alkyl groups to guanine residues in DNA
- Cross-link DNA strands –> prevents uncoiling of DNA in replication
- Trigger apoptosis (via checkpoint pathway)
e. g Chlorambucil, cyclophosphamide, dacarbazine, temozolomide.
how do Pseudo-alkylating agent work?
o Same mechanism of cell death as alkylating agents
–> but Add platinum to guanine residues in DNA–> triggers apoptosis
o E.g: carboplatin, cisplatin, oxaliplatin
What are side effects of alkylating + pseudoalkylating agents?
- hair loss (not carboplatin),
- nephrotoxicity,
- neurotoxicity,
- ototoxicity (platinum),
- nausea,
- vomiting,
- diarrhoea,
- immunosuppression,
- fatigue
What are Anti-metabolites?
How do they work?
- they are purine/pyrimidine analogues
- Masquerade as purine or pyrimidine residues–> inhibition of DNA synthesis, DNA ds-breaks, and apoptosis
- Block DNA replication + transcription
- Can be purine (A/G), pyrimidine (C/T/U) or folate antagonists
e. g methotrexate, 6-mercaptopurine, dacarbazine, and fludarabine, 5-fluorouracil, capecitabine, gemcitabine
What are side effects of Anti-metabolites?
o Hair loss (alopecia) – not 5FU or capecitabine
o Bone marrow suppression à anaemia, neutropenia, and thrombocytopenia
o Increased risk of neutropenic sepsis (and death) or bleeding
o Nausea/vomiting (dehydration)
o Mucositis + diarrhoea
o Palmar-plantar erythrodysesthesia (PPE) – red hands/feet
o Fatigue
What are Anthracyclines?
How do they work?
- Inhibit transcription + replication by intercalating (i.e. inserting between) nucleotides in DNA/RNA strand.
–> Also block DNA repair - mutagenic
–> They create free oxygen radicals –> damage DNA + cell membrane
e.g doxorubicin, epirubicin
what are side effects of Anthracyclines?
o Cardiac toxicity (arrythmias, HF) – due to free radical damage(?) –> due ECHO before starting treatment
o Alopecia/hair loss
o Neutropenia
o Nausea/Vomiting
o Fatigue
o Skin changes
o Red urine
What are vinca alkaloids + taxanes?
How do they work?
- they re Originally derived from natural sources
- -> Works by inhibiting assembly (vinca alkaloids) or disassembly (taxanes) of mitotic microtubules –> cause dividing cells to undergo mitotic arrest
- -> microtubule targeting drugs
What are side effects vince alkaloids + taxanes?
o Nerve damage: peripheral neuropathy (tingling), autonomic neuropathy
o Hair loss
o Nausea + Vomiting
o Bone marrow suppression (neutropenia, anaemia etc)
o Arthralgia
o Allergy
What are topoisomerase inhibitors?
How do they work?
Normally = Topoisomerases prevent DNA torsional strain in replication + transcription
o They induce temporary single strand (topo1) or double strand (topo2) breaks in phosphodiester backbone
- They protect free ends of DNA from aberrant recombination events
- Drugs e.g. anthracyclines –> also have anti-topoisomerase effects
e. g Topotecan and irinotecan (topo I) + etoposide (topo II) alter binding of topoisomerase complex to DNA –> allow permanent DNA breaks
What are side effects of topoisomerase inhibitors?
o (irinotecan): Acute cholinergic type syndrome – diarrhoea, abdominal cramps, and diaphoresis (sweating). Therefore, given with atropine
o Hair loss
o Nausea, vomiting
o Fatigue
o Bone marrow suppression
What are some resistance mechanisms ?
- Drug effluxed from cell by ATP-binding cassette (ABC) transporters
- DNA adducts replaced by Base Excision repair (using PARP)
- DNA repair mechanisms upregulated –> damage repaired –> prevents DNA ds-breaks
What are targeted therapies?
Cancer cells have wiring, but can cut wiring in monogenic cancers
- But if cut one path –> parallel pathways or feedback cascades may be activated
- Dual kinase inhibitors being developed – prevent feedback loops but increase toxicities
What are the 10 hallmarks of cancer cells ?
- Self –sufficient: survives with minimal stimulation
- Insensitive to anti-growth signals: grows regardless of intake
- Anti-apoptotic
- Pro-invasive + metastatic
- Pro-angiogenic
- Non-senescent
- Dysregulated metabolism
- Evades immune system
- Unstable DNA
- Inflammation
Over expression of receptor causes:
a) HER2
b) EGFR
c) PDGFR
Over expression of ligand causes:
d) VEGF
Over expression of receptor causes:
a) HER2 – breast cancer
b) EGFR – breast + colorectal cancer
c) PDGFR- glioma (brain cancer)
Over expression of ligand causes:
d) VEGF - prostate, kidney, breast cancer
–> over expression causes increase in kinase cascade and signal amplification
Constitutive (ligand-independent) receptor activation:
- EGFR (lung cancer)
- FGFR (head + neck cancers, myeloma)
-
Monoclonal antibodies:
how do humanized vs chimeric antibodies differ?
Humanized monoclonal antibody, murine regions (black) interspersed within the light (light gray) and heavy (dark gray) chains of the Fab portion.
Chimeric antibody murine component (black) of the variable region of the Fab section is maintained integrally.
Monoclonal antibodies target extracellular component of receptor. They act by which 4 mechanisms?
- Neutralise ligand
- Prevent dimerization of receptors
- Internalisation of receptor
- Also, activate Fcγ-receptor-dependent phagocytosis or cytolysis induces complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC)
What do Small molecule inhibitors (SMIs) do?
- they Bind to kinase domain of tyrosine kinase in cytoplasm –> block autophosphorylation + downstream signalling
- E.g. glivec (imatinib) for CML targeted BCR-ABL fusion protein – specifically targets ATP-binding region in kinase domain –> inhibits kinase activity of ABL1
–> also acts on intracellular kinases –> ca affect cell signalling pathways
Small molecule inhibitors (SMIs) 2 different modes of action
- Receptor-inhibiting examples: erlotinib (EGFR), gefitinib (EGFR), lapatinib (EGFR/HER2), sorafinib (VEGFR)
- Intracellular kinase-inhibiting examples: Sorafinib (Raf kinase), Dasatinib (Src kinase), Torcinibs (mTOR inhibitors)
What are 4 main resistance mechanisms to targeted therapies?
- Mutations in ATP-binding domain (BCR-Abl fusion gene/ALK gene, Glivec + crizotinib respectively)
- Intrinsic resistance (herceptin effective only in 85% HER2+ breast cancers, suggesting other driving pathways)
- Intragenic mutations
- Upregulation of downstream or parallel pathways
