Drugs used in cancer chemotherapy Flashcards
Chemotherapy is used on its own as a treatment for cancer. T/F?
False. Chemotherapy is usually (almost always) used in conjunction with other treatments.
Describe the mechanism of action of alkylating agents
Alkylating agents:
- Two types: classical alkylating (e.g. nitrogen mustards) and platinum based drugs (ending in “platin” e.g. cisplatin)
- not dependent of cell cycle phase
- alkylate DNA at guanine bases to form DNA adducts or DNA strand cross links
- base excision repair of guanine adducts can lead to strand breaks
- cross linked DNA cannot be replicated or transcribed
- DNA damage and cell death occurs INDEPENDENT of cell cycle
- effects are DOSE DEPENDENT
Describe the mechanism of action of anti-metabolites
Anti-metabolites:
- Deprive cells of building blocks required for growth and division
- Affect DNA synthesis by acting as a substitute to the actual metabolites that would be used in the normal metabolism
- Target cells in S-phase
- Two types: folic acid antagonists and DNA base analogues
Folic acid antagonists:
- Deplete folate needed for purine synthesis by blocking dihydrofolate reductase (DHFR)
e. g. Methotrexate
DNA base analogues:
- Disrupt DNA synthesis and function by substituting DNA bases with pyrimidine, purine and nucleoside analogues
e. g. 5-Fluorouracil (5FU) - non-phase dependent (independent of cell cycle)
Describe the mechanism of action of mitotic inhibitors
Mitotic inhibitors:
- Interfere with mitotic spindle by targeting microtubules
- Two types: Vinca alkaloids and Taxanes
- Both come from PLANTS
- Affect cells in M-phase
Vinca Alkaloids:
- Periwinkle plant extract
- Binds tubulin to prevent microtubule and mitotic spindle formation
- i.e. stops FORMATION of microtubule
e. g. Vincristine
Taxanes:
- Pacific yew bark extract
- Bind microtubules to prevent their disassembly at mitosis
- i.e. stops DISASSEMBLY of microtubules
e. g. Paclitaxel
Describe the mechanism of action of cytotoxic antibiotics
Cytotoxic antibiotics
- Naturally derived from micro-organisms
- Two types: Anthracyclines and bleomycins
- (note: link between antibiotics and suffixes -cyclines and -mycins)
- Affect cells in G2 phase
Anthracyclines:
- Prevent DNA replication by intercalation between base pairs and inhibition of topoisomerase II
- cardiotoxic
- non-phase dependent (independent of cell cycle)
e. g. Doxorubicin
Bleomycins:
- Prevent DNA replication by inducing single and double strand DNA breaks
- causes pulmonary fibrosis
e. g. Bleomycin A2 and B2
Describe the mechanism of action of hormones in chemotherapy
Hormones in chemotherapy:
- Hormone therapy blocks the effect or production of hormones that are known to stimulate tumour growth (e.g. oestrogen and androgens)
- Also used to kill off cells (corticosteroids)
Breast cancer:
- Anti-oestrogens (e.g. Tamoxifen) block oestrogen receptors
- Aromatase inhibitors prevent the conversion of androgens to oestrogen
Prostate cancer:
- Anti-androgens block androgen receptors
Lymphoid cancers (lymphoma, leukaemia):
- Corticosteroids kill lymphocytes (lymphocytolytic effect)
- Corticosteroids affect cells in G1 phase
What cells do traditional chemotherapeutic agents target and what does this mean for the specificity and side effects of the treatment?
Target highly proliferative cells therefore chemotherapy isn’t specific to cancer cells.
Highly proliferative normal tissues such as GI tract epithelial cells, hair follicles, bone marrow/haemopoeitic cells are also affected.
This results in side effects including GI toxicity (vomiting/nausea/diarrhoea), hair loss, myelosuppression leading infection, anaemia and bleeding.
Explain the concept of “proportional killing” in traditional chemotherapeutic drugs
- Traditional chemotherapy drugs only affect a proportion of cancer cells
- i.e. a drug with 99.9% success rate will kill 99.9% of the tumour cells
- This means that chemotherapy does not completely eradicate the tumour, it reduces its size so that it is no longer clinically detectable (i.e. remission)
- It is possible for the remaining cells to grow or stay dormant and re-activate (other possibility is that they are killed off by immune system)
- A combination of therapies and targeted delivery is needed for complete eradication
What are some of the specific side effect of chemotherapeutic drugs?
Alkylating agents:
- Cyclophosphamide (a nitrogen mustard, one of the classical alkylating agents): haemorrhagic cystitis
- Cisplatin (a platinum based drug): neurotoxicity, nephrotoxicity and ototoxicity
Anti-metabolites:
- methotrexate (a folic acid antagonist): hepatic damage
- 5-fluorouracil (a DNA base analogue): skin pigmentation
Mitotic inhibitors:
- neurotoxicity
Cytotoxic antibiotics:
- Bleomycin: pulmonary fibrosis
- Antracyclines: cardiomyopathy
What is the rationale behind the development of targeted therapies in cancer treatment?
- Chemotherapy kills fast growing normal cells as well as cancer cells - causes serious side effects and limits effective dosing
- Efficacy is limited in most tumour types (drugs are not 100% effective)
Need to develop drugs targeted to cancer-specific mutations & to identify biomarkers to select patients with those mutations
Give an example of targeted therapy in cancer and briefly outline the mechanism.
Tyrosine kinase inhibitors:
- Growth factor receptors are activated in many tumours
- Many growth factor receptors are tyrosine kinase receptors
- Blocking tyrosine kinase receptors inhibits cancer growth signalling
- Ways of blocking TK receptors include intracellular mechanisms (small molecule inhibitors bind kinase domain) and extracellular mechanisms (antibodies block specific proteins)
What is the biggest problem with Kinase Inhibitors?
Development of resistance to inhibitor
- can be primary (seen in 1st dose) or acquired (develops during treatment)
- can develop simultaneously to multiple drugs
List the phase independent drugs.
Alkylating agents
5-fluorouracil
Anthracyclines
What is the classic mechanism of anticancer drug action?
Interference with DNA synthesis and/or function induces apoptosis and causes cell death.
