10-11-22 – Cancer Chemotherapy Flashcards
Learning outcome
- To review the mechanisms of action of anticancer drugs introduced in MD2002
- To review the limitations of current cancer chemotherapy
- To introduce new molecularly targeted anticancer drugs in common usage and the associated mutational efficacy profile of the cancers treated
How do antimicrobial and anti-cancer drugs compare in terms of
* Immune response
* Body defences
* % Kill needed
* Biochemistry
What are the 3 main approaches to dealing with established cancers?
- 3 main approaches to dealing with established cancers:
1) Surgical excision
2) Radiotherapy
3) Chemotherapy
What are 4 types of traditional agent chemotherapy drugs?
- 4 types of traditional agent chemotherapy drugs:
1) Alkylating agents
2) Antimetabolites
3) Cytotoxic antibiotics
4) Plant derivatives
What are alkylating agents used for?
How do they function?
How can they link to strands of DNA? What does this cause?
- Alkylating agents are the most commonly employed anti-cancer drug
- These are compounds which have the property of forming covalent bonds with suitable nucleophilic substances in the cell under physiological conditions
- They can cause intrastrand linking and cross-strand linking of DNA
- This binding to DNA stops the replication of cancer cell DNA
What are the 6 major groups of alkylating agents?
What is an example of each?
- 6 major groups of alkylating agents
1) Nitrogen mustards – e.g. cyclophosphamide
2) Ethylenimines - e.g. Thiotepa
3) Alkylsulphonates - e.g. Busulphan
4) Hydrazines and Triazines – e.g. Temozolomide
5) Nitrosoureas – e.g. lomustine, carmustine
6) Platinum based compounds – e.g. cisplatin
What are the 3 major groups of antimetabolites?
What is an example of each?
- 3 major groups of antimetabolites
1) Antifolates – e.g. methotrexate
2) Antipyrimidines – e.g. 5-FU, gemcitabine
3) Antipurines – e.g. mercaptopurine, thioguanine
What are cytotoxic antibiotics?
How do cytotoxic antibiotics work?
What are 4 types of cytotoxic antibiotics?
- Cytotoxic antibiotics are antitumour antibiotics produce their effects mainly by direct action on DNA
- 4 types of cytotoxic antibiotics:
1) Anthracyclines - e.g. doxorubicin.
2) Dactinomycin
3) Bleomycin
4) Mitomycin
What are plant derivatives?
How 2 ways do plant derivatives work?
What are 4 types of plant derivatives?
What is an example of each?
What is their mechanism of action?
- Plant derivatives are spindle poisons (inhibitors)
- Plant derivatives work by affecting microtubule function and preventing mitotic spindle formation or top I/ II inhibitors (topoisomerase enzymes related to DNA replications)
- 4 types of plant derivatives:
1) Vinca alkaloids, e.g. vincristine, vinblastine - spindle
2) Taxanes e.g Paclitaxcel (taxol), docetaxel - spindle
3) Camptothecins e.g. irinotecan – top I
4) Etoposide – DNA binding/ top II
What are the 6 main drawbacks of chemotherapy drugs?
- 6 main drawbacks of chemotherapy drugs:
1) Target cell proliferation not the more lethal properties of invasiveness and metastasis
2) Non-specific cell killers rather than being aimed at the particular changes which make a cell malignant
3) The development of resistance (particularly multidrug resistance) to anticancer drugs
4) Leaves some remaining cells
5) Side effects
6) Patients not completing therapy regimen due to side effects
What cells are targeted with chemotherapy drugs?
What 4 types of healthy cells have high rates of growth and proliferation?
What do side effects often relate to?
How do side effects vary?
What are 3 examples of drug specific side effects?
When do side effects often occur? How is this prevented?
- Cells with high rates of growth proliferation are targeted with chemotherapy drugs
- Healthy cells which have a high rate of growth and multiplication include cells of the:
1) Bone marrow
2) Hair
3) GI mucosa
4) Skin - Therefore, side-effects often relate to these body systems
- Severity of side effects varies between drugs, and may be drug specific
- 3 examples of drug specific side effects:
1) Anthracyclines and cardiotoxicity
2) Vinca alkaloids and neuropathy
3) High dose cisplatin and ototoxicity (hearting/balance issues due to medicine) - Side effects often occur 7-14 days post treatment.
- These can be cumulative over many cycles of medicine
- To prevent this, chemotherapy drugs are often not taken individually – there are several chemotherapy drugs along with several drugs prescribed to manage side effects
What is Tumour Lysis syndrome?
Why does it occur?
What 4 things is it characterized by?
When 3 things can it lead to if untreated?
How can we prevent this form happening?
- Tumour lysis syndrome is an acute side-effect of chemotherapy drugs and a metabolic emergency
- It occurs due to rapid cell lysis (death) & large amounts of cell metabolites in blood.
- Tumour lysis syndrome is characterized by:
1) Hyperuricaemia (an abnormally high level of uric acid in the blood)
2) Hyperphosphataemia
3) Hyperkalaemia
4) Hypocalcaemia - If untreated, tumour lysis syndrome can lead to:
1) Acute renal failure
2) Cardiac arrest
3) Death - To try and prevent this, we need to risk assess patient prior to chemotherapy
- We also need to monitor and respond to deranged urea and electrolytes / fluid balance: dialysis may be required
How can chemotherapy drugs affect bone marrow?
What is myelosuppression?
When is it common?
Which cells in the bone marrow are affected?
What 2 ways can we prevent myelosuppression?
- Chemotherapy drugs can cause myelosuppression
- Myelosuppression is reduced production of cells which provide immunity, oxygen transport and clotting
- It is common with many chemotherapy agents (except Vincristine and Bleomycin)
- Only actively dividing cells in the bone marrow are affected (i.e. stem cells), and cells with shorter life span due to high proliferation rate
- 2 ways we can prevent myelosuppression:
1) Monitor full blood count prior to then daily during treatment cycles
2) Occasional use of recombinant human granulocyte-colony stimulating factors (e.g. Filgrastim) recommended to reduce incidence/duration of myelosuppression
What are 5 GI side effects of chemotherapy agents?
- 5 GI side effects of chemotherapy agents:
1) Nausea and vomiting
2) Loss of appetite
3) Constipation
4) Diarrhoea
5) Ulceration, dry mouth, pain, taste alterations due to mucositis (lining of GI becomes inflamed)
What are different emetogenic qualities of chemotherapy agents?
What are 3 different treatment options?
- Chemotherapy agents vary in their emetogenic potential (nausea and vomiting – GI Issues)
- Highly emetogenic – cisplatin
- Moderately emetogenic – doxorubicin
- Mildly emetogenic – etoposide
- 3 different treatment options:
1) Low dose benzodiazepine (e.g. lorazepam)
2) Use of steroids (e.g. dexamethasone)
3) Use of anti-emetics such as 5HT3-receptor antagonists (e.g. ondansetron or metoclopramide).
What are novel targeted agents?
What do they exist as?
What are 3 examples of novel targeted agents?
What is their mechanism of action?
What are they each used for?
- Novel targeted agents are a different section of highly engineered protein specific anti-cancer drugs
- They exist as monoclonal antibodies and small molecules
- 3 examples of novel targeted agents and their mechanism of action:
1) Rituximab
* Targets a B cell surface protein
* Used for B cell lymphomas
2) Trastuzumab (Herceptin)
* Targets epidermal growth factor receptor 2 (HER2/ ERBB2)
* Used for breast cancer
3) Imatinib (Gleevec)
* Inhibits BCR-ABL gene signalling pathways
* Used for chronic myeloid leukaemia.
What do personalised medicines take into account?
What 3 things were traditionally used?
What 3 things are used now?
- Personalised medicines take into account individual genetic differences
- 3 things that were traditionally used:
1) Family history
2) Socioeconomic circumstances
3) Environmental factors - 3 things that are used now:
1) Genomic/genetic testing
2) Proteomic profiling
3) Metabolomic analysis (study metabolites)
What are the dangers of drugs?
What are the old, new, and future paradigms (in picture)?
- 6.7% of patients in hospitals experience serious drug reactions because they are reacting to a drug that is fine for most people, but is creating serious effects for them
What are 3 personalised treatments for non-small cell lung cancer (NSCLC)?
What mutations are they each used for?
What type of mutations are these?
How are these mutations linked?
- 3 personalised treatments for non-small cell lung cancer (NSCLC):
1) EGFR mutation analysis: activating mutations – use erlotinib
* EGFR is a growth factor receptor involved in proliferation
* EGFR gene coding for EGFR protein can be sequenced
* Active mutations change proteins to be in an active configuration
2) KRAS mutation analysis: activating mutations – not drug
3) ALK rearrangement analysis: (4%) fusion - use crizotinib
- ALK rearrangements are mutually exclusive with EGFR or KRAS mutations
What is a treatment used in Colorectal cancer?
How does the use of Cetuximab differ based on certain mutations?
What is an example for screening for predisposition mutations?
- Cetuximab is an anti-EGFR monoclonal antibody therapy used in the treatment of colorectal cancer
- We can conduct a KRAS/ NRAS mutation analysis
- If there are no mutations, we used cetuximab plus chemotherapy
- The presence of a RAS mutation predicts the lack of response to therapy
- An example of screening for predisposition mutations is screening for Hereditary Non-Polyposis Colorectal Cancer (HNPCC)
- In NHS Lothian, there is screening for HNPCC in all patients diagnosed with colorectal cancer before the age of 60.
- Immunohistochemistry for four mismatch repair genes and BRAF mutational analysis is undertaken
What is melanoma?
What mutations can melanomas be associated with?
Often, what is this mutation a result of?
What are 3 ways our treatment of melanoma can vary depending on mutation analysis?
- Melanoma is a common and often fatal skin cancer where the cancer cells have frequent genetic mutations
- Approximately 40 to 60% of cutaneous melanomas carry mutations which activate a gene called BRAF, which then leads to further tumour growth.
- The vast majority (80 to 90%) of these BRAF-activating mutations are the result of a small change in one tiny section of DNA.
- 3 ways our treatment of melanoma can vary depending on mutation analysis:
1) BRAF mutation analysis: activating mutations – use vemurafenib (second line therapy)
* Vemurafenib: inhibitor of mutated B-Raf (BRAFV600E)
2) NRAS mutations: - use MEK inhibitors / combinations (clinical trials)
3) KIT (c-Kit) mutations (3% melanomas) - use imatinib
What is BRAF mutation analysis used for?
What is BRAF mutation associated with?
- BRAF mutation analysis is offered as an aid for the pathological diagnosis and subsequent management of patients with suspected papillary thyroid cancer.
- BRAF mutation is associated with an aggressive tumour phenotype and higher risk of recurrent and persistent disease
What are anti PD-1 / PD-L1 drugs?
What is their mechanism of action?
What is an example of this type of drug?
What 2 things is it used for?
- Anti-PD-1/ PD-L1 are a new class of checkpoint inhibitor drugs that target surface protein PD-L1, which is related to how the immune system sees tumour cells
- This is a mechanism used by cancer cells to evade the immune response – this is done by having a blocking effect on interaction of PD-L1 on tumour cells and PD-1 on T-cells
- These anti PD-1 /PD-L1 drugs prevent this blocking and restore antitumour immunity
- An anti PD-1/PD-L1 drug called Nivolumab (checkpoint inhibitor antibody) can be used for:
1) Melanoma
2) NSCLC (non-small cell lung cancer)
What is CTLA-4?
What do Anti-CTLA-4 antibodies do?
What is an example of a medication used?
When can it be used?
- CTLA-4 is a surface receptor protein on T-cells that antigen presenting cells can bind to in order to inhibit T cells
- Anti CTLA-4 antibodies (such as the medicine ipilimumab) can bind to the CTLA-4 receptor protein, blocking it from being interacted with by antigen presenting cells
- This allows for tumour cells to be killed
- Ipilimumab can be used to treat metastatic melanoma
