Chemotherapy Flashcards
What are antimetabolites?
Methotrexate
5-fluorouracil
Methotrexate mechanism
Competitive inhibitor of dihydrofolate reductase (DHFR), close structural analogue of folic acid.
Inhibits biosynthesis of purines and dTMP - hence inhibits RNA synthesis and DNA replication
What other diseases is methotrexate used for as well as cancer?
Malaria, psoriasis, rheumatoid arthritis
5-fluorouracil action
Antimetabolite drug converted in vivo to FdUMP, which inhibits thymidylate sythase (TS)
What are alkylating/platinum drugs?
DNA damage leads to cell cycle arrest apoptosis
Cyclophosphamide
Cisplatin
What are topoisomerase inhibitors?
DNA damage via direct binding to DNA
Doxorubicin
Cyclophosphamide action
Alkylating agent
Displacement of each chlorine atom allows covalent cross-linking between N7 nitrogen’s of guanine bases.
What drug is similar to mustard gas?
Cyclophosphamide
What other diseases is cyclophosphamide used to treat?
Also active in autoimmune diseases (lupus, rheumatoid arthritis)
What selectivity does cyclophosphamide give?
Detoxification of aldophosphamide intermediate by aldehyde dehydrogenase (ALDH) confers some selectivity for cells with low ALDH.
Cisplatin action
Alkylating agent
Displacement of chloride ligand by water allows cross-linking of DNA bases by platinum
Intra-strand DNA crosslinks account for most of the cytotoxicity
Cisplatin structure
Central Pt with 2 Cl and 2 NH3
Doxorubicin action
Topoisomerase inhibitor
DNA intercalating anthracycline inhibits cellular enzyme DNA topoisomerase II, stabilising a reaction intermediate in which both DNA strands are broken.
Proteolytic processing of this ‘cleavable complex’ frees the double-strand breaks
What are anti-mitotic agents?
Inhibit stages of mitosis
Vincristine
Taxanes
Vincristine action
Anti-microtubule agent: inhibits tubulin polymerisation in a manner similar to colchicine
prevents assembly of mitotic spindle
arrests cells in metaphase
selectively toxic to cells with defective ‘spindle attachment’ checkpoint
Taxane action
Stabilises microtubules so they cannot be disassembled
Neoadjuvant chemo
chemotherapy before surgery
reduces size of local disease; early treatment of micro metastases
Adjuvant chemo
chemotherapy after surgery
early treatment of micrometastases
Palliative chemo
reduce tumour bulk
slow the growth of existing lesions
delay development of new lesions
relieve symptoms
Side effects of chemotherapy
Immunosuppression and myelosuppression
Neutropenic enterocolitis
Gastrointestinal distress
Anemia
Nausea and vomiting
Hair loss
Infertility
Neuropathy
Vascular damage
Cardiotoxicity
What can neutropenia lead to?
Neutropenia (a decrease of the neutrophil granulocyte count below 0.5 x 109/litre) can result in neutropenic sepsis and is a common cause of morbidity and mortality
How can low neutrophil count be counteracted with other drugs?
Can be improved with synthetic G-CSF (granulocyte-colony-stimulating factor, filgrastim, lenograstim).
What is CAV therapy? Why give combination therapy?
Reduces resistance
CAV therapy (small cell lung cancer): cyclophosphamide, adriamycin (doxorubicin) and vincristine.
How can therapy cause tumorigenesis?
Most therapies are tumorigenic
What is a hormonal therapy?
Tamoxifen
Tamoxifen action
Metabolised to hydroxytamoxifen, an oestrogen receptor (ER) antagonist
Binds to ER, recruits co-repressor proteins and inhibits ER-dependent transcription
Arrests growth of ER-positive breast cancer
Aromatase inhibitors
Aromatase inhibitors (e.g. letrozole) block peripheral oestrogen synthesis in post-menopausal women
Imatinib (gleevec)
Inhibitor of tyrosine kinase activity
Very high response rates in early-phase CML (BCR-ABL)
also effectively inhibits KIT tyrosine kinase in gastro-intestinal stromal tumour
Herceptin (trastuzumab)
Humanised monoclonal antibody against the extracellular domain of HER2, down-regulates HER2-dependent mitogenic signalling, may also induce antibody-dependent cellular cytotoxicity (ADCC)
HER2 in breast cancer?
A member of the epidermal growth factor receptor (EGFR) family of transmembrane receptor tyrosine kinases.
Overexpressed, often as a result of gene amplification, in ~25% of breast cancers, overexpression of HER2 drives inappropriate cell proliferation - associated with poor prognosis.
