S7) Cancer Chemotherapy Flashcards
What is the aim of chemotherapy?
The aim of chemotherapy is to kill/prevent replication of tumour cells at a greater rate than normal healthy tissue
What is the role of chemotherapy?
- Curative
OR
- Palliative
When is chemotherapy usually given?
- Given as an adjunct to surgery/radiotherapy
OR
- Given in isolation
which phase of the cell cycle cannot be targeted in chemotherapy
G0 → when there is no proliferation
what is growth fraction
proportion of cells dividing at any given time, the higher the growth fraction the more cells you can target
→ tumours are heterogeneous (some cells proliferate, die or are dormant) so repeated cycles are required to eradicate remaining and re growing cells
What are the factors leading to increased tumour growth?
- Increased growth fraction
- Decreased duration of cell cycle
- Decreased rate of cell loss
why do we give chemo in a pulse like form
overall the destruction of the tumour cells is far greater than bone marrow cells. The timing is so the tumour cells don’t have time to recover before each next dose but the bone marrow cells do
How can one classify tumours according to chemosensitivity?
- High sensitivity
- Modest sensitivity
- Low sensitivity (have to use other modes of treatment)
Identify five types of high sensitivity tumours
- Lymphomas
- Germ cell tumours
- Small cell lung tumours
- Neuroblastoma
- Wilm’s tumour
Identify five types of modest sensitivity tumours
- Breast tumours
- Colorectal tumours
- Bladder tumours
- Ovary tumours
- Cervix tumours
Identify four types of low sensitivity tumours
- Prostate tumours
- Renal cell tumours
- Brain tumours
- Endometrial tumours
Identify the four groups of chemotherapy
- Antimetabolites
- Antibiotics
- Alkylating/Platinating agents
- Mitotic spindle inhibitors
Provide two examples of alkylating/platinating agents
- Platinating – Cisplatin, oxaliplatin
- Alkylating – nitrogen mustards e.g. Chlorambucil
Describe the mechanism of action of alkylating/platinating agents
- Target DNA synthesis in G1/S phase
- Forms inter and intrastrand adducts (covalent bonds) with DNA nucleosides disrupting structure and preventing replication and so they die
Identify some specific ADRs of alkylating/platinating agents
- Peripheral, sensory and motor neuropathy
- High frequency ototoxicity
Describe the three possible mechanisms of resistance to alkylating agents
- Decreased entry or increased exit of agent
- Inactivation of agent in cell
- Enhanced repair of DNA lesions produced by alkylation
name two anti-metabolites
5-fluorouracil: inhibits pyrimidine synthesis via inhibiton of thymidylate synthase
Metrotrexate: inhibits purine synthesis via inhibition of dihydrofolate reductase
Provide some examples of microtubule poisons
- Vinca Alkaloids
- Taxanes
Describe the mechanism of action of microtubule poisons
- Target tubulin proteins in the mitotic phase
- Chromosomes can’t align and separate into two daughter cells in synchrony
How do microtubule-binding agents affect microtubule dynamics?
- Inhibit polymerisation: Vinca Alkaloids
- Stimulate polymerisation and prevent depolymerisation: Texanes
how can cancer cells become resistant to some chemo drugs
→ body has its own repair system
→ cell cytoplasm has a P glycoprotein, these recognise foreign substances inside the cell and pump it out the cell
→ chemo drug is seen as foreign and can be pumped out cell
→ agents inside the cell (glutathione) is within the cytoplasm to mop up foreign material
Identify the specific ADR of microtubule poisons
Neurotoxicity: glove and stocking peripheral neuropathy
Provide an example of a glycopeptide antibiotic
Bleomycin
Describe the mechanism of action of glycopeptide antibiotics
Most effective in G2 stage:
- Forms free radicals when chelated with Fe2+ which attack phosphodiester bonds in DNA
- Results in cutting (scission) of DNA strands
Identify the specific ADR of glycopeptide antibiotics
Pulmonary Fibrosis (10%)
Provide an example of an anthracycline antibiotic
Doxorubicin
Describe the mechanism of action of anthracycline antibiotics
Targets DNA synthesis in “S” phase:
- Intercalate between the base pairs in DNA which interferes with transcription/replication
- Topoisomerase II inhibition
- Generate free radicals – damage DNA
Identify the specific ADR of anthracycline antibiotics
Cardiotoxic
Provide two examples of antimetabolites
- Methotrexate
- 5-Fluorouracil
What is the mechanism of action of methotrexate?
Methotrexate inhibits dihydrofolate reductase, preventing DNA synthesis
What is Tamoxifen?
Tamoxifen is a SERM (selective oestrogen receptor modulator) and acts as antagonist of the oestrogen receptor in breast tissue
Describe the metabolism of Tamoxifen
Tamoxifen is a prodrug and is metabolised by liver to its active form which can competitively bind to oestrogen receptors
Describe the mechanism of action of Tamoxifen
Tamoxifen causes cells to remain in the G0 and G1 phase of the cell cycle
When can Tamoxifen therapy be used?
To be eligible for therapy those with breast cancer must be ER (oestrogen receptor) positive
Identify some common side effects of Tamoxifen treatment
- Hot flushes/sweats
- Increased DVT/PE risk
- Weight gain
- Increased risk of endometrial cancer → while it blocks oestrogen in the breast in the endometrium tamoxifen is a oestrogen agonist so increases the amount of oestrogen in uterus
What is the predicted response to chemotherapy dependent on?
- Performance score
- Clinical stage
- Prognostic factors/score
- Molecular / cytogenetic markers
What are the different routes of administration for chemotherapy?
- IV
- PO
- SC (community setting)
- Into a body cavity (bladder, pleural effusion)
- Intralesional
- Intrathecal (lumbar puncture / omaya reservoir – directly into ventricles)
- Topical
- IM (rarely)
Identify some common side effects of chemotherapy
affects areas of the body that are fast replicating
what is a common side effect of the chemo drug bleomycin
pulmonary fibrosis
alopecia
→ hair thins 2-3 weeks
→ minimal with platinums
→ can wear scalp cooling hats to minimise hair loss
what are some skin side effects of chemo drugs
Local:
→ irritation and thrombophlebitis of veins, extravasation
- bleomycin (drug): hyperkeratosis, hyperpigmentation and pressure sores
- hyperpigmentation
Explain how acute renal failure occurs as a side effect of chemotherapy
Acute renal failure – hyperuricaemia caused by rapid tumour lysis leads to precipitation of urate crystals in renal tubules
→ cell break down releases cytokines that can cause crystals in the blood and block kidneys = rapid tumour lysis syndrome
risks of chemo meds on GI tract
→ perforation at the site of the tumour = bad so need artificial feeding
why does vomiting occur in chemo
→ triggers chemoreceptors in Brain and trigger them
Vomiting is multifactorial but includes direct action of chemotherapy drugs on the central chemoreceptor trigger zone.
What are the different patterns of emesis?
- Acute phase (4 - 12 hours)
- Delayed onset (2 - 5 days later)
- Chronic phase (persist up to 14 days)
Mucositis is due to GI tract epithelial damage.
Where does it commonly occur?
- May be profound and involve whole tract
- Commonly worst in oropharynx
Mucositis is due to GI tract epithelial damage.
How does this present?
- Sore mouth/throat
- Diarrhoea
- G.I. bleed
What causes variability in the pharmacokinetics of chemotherapy?
- Abnormalities in absorption
- Abnormalities in distribution
- Abnormalities in elimination
- Abnormalities in protein binding
What is the result of the abnormalities in absorption?
- Nausea
- Vomiting
- Compliance
- Gut problems
What is the result of the abnormalities in distribution?
- Weight loss
- Reduced body fat
- Ascites
What is the result of the abnormalities in elimination?
- Liver dysfunction
- Renal dysfunction
- Other medication
What is the result of the abnormalities in protein binding?
- Low albumin
- Other drugs
Other drugs may increase plasma levels of the chemotherapy drug.
What are the important drug reactions that should be considered during chemotherapy?
- Vincristine and itraconazole (common antifungal)
- Capecitabine (oral 5FU) and warfarin
- Methotrexate and penicillin, NSAIDs
- Capecitabine and grapefruit juice
Which three factors should be monitored during chemotherapy treatment
- Response of cancer – radiological imaging, tumour marker blood tests, bone marrow/cytogenetics
- Drug levels
- Organ damage – creatinine clearance, echocardiogram
What principles can one learn from the fractional kill hypothesis?
- Bone marrow cells recover quicker than tumour cells
- Hence a new dose of chemotherapy is given after bone marrow regeneration has occurred
Provide two examples of vinca alkaloids
- Vincristine
- Vinblastine
name two anti-metabolites
5-fluorouracil: inhibits pyrimidine synthesis via inhibiton of thymidylate synthase
Metrotrexate: inhibits purine synthesis
problems that arise with combination therapy
→ if both drugs have similar side effects then you have to lower both doses but then they will have less of a treatment effect
what causes variability of different chemo drug
what are some drug-drug interactions involved In chemo drugs
What are some ways you can monitor chemo treatment
→ radiological imaging, tumour marking, bone marrow
→ measure drug levels (methotrexate) and folic acid residue
→ check for organ damage (heart: creatinine clearance and echo)
