Anti-cancer chemotherapy Flashcards
What are the general classes of anti-cancer drugs?
- Cytotoxic drugs (inhibits process of cell division)
- Hormones
- Protein kinase (small molecule) inhibitors
- Monoclonal antibodies
What are the classes of cytotoxic drugs?
- Alkylating/cross-linking agents
- Anti-metabolites
- Anti-mitotic drugs
What are the classes of alkylating/cross-linking drugs?
- Nitrogen mustards
- Nitrosureas
- Aziridines
- Platinum compounds
- Anthracyclines
What is the mechanism of action of nitrogen mustards?
Alkylating agents form highly reactive carbonium ions (usually 2) that are able to:
- Cross-link nucleotide bases within the same strand of DNA or across different strands. This inhibits DNA replication/transcription.
- If first carbonium alkylates guanine and second carbonium ion reacts with water, the monoalkylated guanine may be misread (can pair with thymine) during DNA replication and there may be a GC → AT mutation.
- Alkylated strands are targeted by DNA repair mechanism and so may cause scission and fragmentation of DNA.
What are examples of nitrogen mustards?
- Cyclophosphamide
- Chloambucil
- Melphalan
What is the mechanism of activation of nitrosoureas?
- Capable of alkylating DNA via carbonium ion
- Guanine is preferred target
- Creates interstrand cross-links that inhibit DNA transcription/replication
What are examples of nitrosoureas?
- Carmustine
- Lomustine
- Semustine
What is the mechanism of action of aziridines?
- First bond with DNA formed via reaction with semiquinone following breaking of the aziridine ring
- Second bond formed after displacement of carbamate from aziridine molecule
- Creates intra- and interstrand crosslinks in DNA
What are examples of aziridines?
Mitomycin C
What is the mechanism of action of platinum compounds?
- Plainer compounds with Cl atoms on the same side (Cis)
- Once it enters the cell, the molecule reacts with DNA via 2 mechanisms:
- Via aquo intermediate
- Direct binding - It preferentially binds G and A
- Its primary action is to create intrastrand crosslinks between adjacent G molecules
- Causes bending of the DNA duplex and inhibits action of DNAP
What are examples of platinum compounds?
- Cisplatin
- Carboplatin
- Oxaliplatin
What is the mechanism of action of anthracyclines?
Plainer structures that non-covalent interaction with DNA
- They insert into the spaces between the planes of different nucleotide base pairs in dsDNA following localised partial unwinding.
- Their intercalation into the dsDNA fixes the partially unwound nature of dsDNA, disrupting the sizes of the major/minor grooves in dsDNA.
- The different sized grooves disrupts the binding of DNA/RNA polymerases.
What are examples of anthracyclines?
- Doxorubicin
- Daunomycin
What are the anti-metabolites?
- Methotrexate
- 5-fluorouracil
What is the mechanism of action of methotrexate?
- Inhibition of DHFR
- Inhibits synthesis of purine nucleotides and thymidylate
- Acts as competitive inhibitor of folate transport into mammalian cells
What is the mechanism of action of leucovorin?
- Leucovorin can be given in conjunction with methotrexate as it can be converted to folic acid derivatives
- Allows DNA synthesis to occur in normal cells but small amounts present don’t meet demands of fast dividing cancer cells
What is the mechanism of action of 5-fluorouracil?
- Inhibitor of deoxythymidylate (DTMP) synthesis
- Interacts with thymidylate synthetase but is not converted to DTMP
What are the topoisomerase inhibitors?
- Etoposide
- Topotecan
What is the mechanism of etoposide?
- Inhibitor of topoisomerase II
- Prevents DNA replication
What is the mechanism of topotectan
- Inhibitor of topoisomerase I
What are the classes of anti-mitotic drugs?
- Topoisomerase inhibitors
- Vinca alkaloids
- Taxanes
What is the mechanism of action of vinca alkaloids?
- Binds to free tubulin dimers in the cytosol
- Prevents them from polymerising into microtubule
- Shifts equilibrium of microtubule formation towards depolymerisation
- Disrupts formation of mitotic spindle and thus inhibits cell division
What are examples of vinca alkaloids?
- Vincristine
- Vinblastine
What is the mechanism of action of taxanes?
- Stabilises microtubules and shifts equilibrium towards polymerisation
- Causes formation of abnormal bundles of microtubules that disrupt mitosis and leads to cell death
What are examples of taxanes?
- Paclitaxel
- Docetaxel
- Cabazitaxel
What are the classes of hormone anti-cancer drugs?
- Anti-oestrogens
- Aromatase inhibitors
- GnRH analogues
- Anti-androgens
- Glucocorticoids
What is the mechanism of action of anti-oestrogens?
- Competitive inhibitor of oestrogen receptors (ER)
- Reduces pro-proliferation effects of oestrogen
What are examples of anti-oestrogens?
- Tamoxifen
- Toremifene
- Fulvestrant
What is the mechanism of action of aromatase inhibitors?
- Competitive inhibition of aromatase enzyme and inhibits synthesis of oestrogens in adrenal cortex, fats and muscles
- Effective in post-menstrual women whose ovaries no longer produce oestrogen
What are examples of aromatase inhibitors?
- Anastrozole
- Letrozole
What is the mechanism of action of GnRH analogues?
- Normally, pulsatile release of GnRH stimulates release of LH from the anterior pituitary
- LH stimulates oestrogen release from ovaries and testosterone release from testes
- Continuous stimulation of anterior pituitary by GnRH causes desensitisation and inhibition of LH release
What are examples of GnRH analogues?
- Goserelin
- Buserelin
- Leuprorelin
What is the mechanism of action of anti-androgens?
- Competitive inhibitor of androgen receptor (AR)
- Inhibits activity of testosterone and other androgens
What are examples of anti-androgens?
- Flutamide
- Cyproterone
What is the mechanism of action of prednisone (glucocorticoid)?
- Prodrug that is converted to active prednisolone in liver
- Upregulates expression of anti-inflammatory proteins and suppresses lymphocyte proliferation
What are the monoclonal antibody anti-cancer drugs?
- Rituximab
- Trastuzumab
- Bevacizumab
- Cetuximab
What is the mechanism of action of rituximab?
Humanised monoclonal antibody
- Binds to CD20 on surface of transformed B cells
- Mediates lysis of these B cells through variety of antibody-specific mechanisms
What is the mechanism of action of trastuzumab?
Humanised monoclonal antibody
- Binds to humanised epithelial growth factor 2 (HER2/hEGFR2)
- Inhibits binding of EGF and promotes cell proliferation
What is the mechanism of action of bevacizumab?
Humanised monoclonal antibody
- Binds to and inhibits action of VEGF
- Prevents angiogenesis and thus inhibits tumour growth
What is the mechanism of action of cetuximab?
Human/mouse chimeric monoclonal antibody
Binds to EGFR and inhibits binding of EGF
What are example of a protein kinase (small molecule) inhibitor?
- Imatinib
- Erlotinib
What is the mechanism of action of imatinib?
Inhibitor of EGFR protein kinases:
- Bcr-Abl chimeric protein (chronic myeloid leukemia)
- C-kit
Inhibition is achieved by binding to ATP-binding site
What is the mechanism of action of erlotinib?
- Inhibits EGFR tyrosine kinase
- Prevents down-stream signalling and EGF pro-proliferation signals
