L16 - Chemotherapy Flashcards
Imatinib
Tyrosine kinase inhibitor
Tumour selective (targeted)
Fewer side effects
- blocks the catalytic aspect of tyrosine kinase which prevents the formation of abnormal proteins
- prevents chronic myeloid leukaemia
Purines
Adenine and Guanine
Pyridimines
Cytosine and thymine (uracil in RNA)
Factors that affect tumour growth
- growth fraction
- duration of the cell cycle
- rate of cell loss
Number of cells required for detection of tumour
1 x 10^9
Number of cells of tumour not viable for life
1 x 10^12
- short window for detection
When does Chemotherapy work
Only works when cells are in the cell cycle
Fractional cell kill hypothesis
- When chemotherapy drug is administered tumour cells and other rapidly dividing cells decrease e.g. in bone marrow
- The bone marrow cells recover more quickly than tumour cells therefore the next cycle of chemotherapy is given when bone marrow cells have recovered
- Overall, there is minor reduction in bone marrow cells therefore give supportive treatment
Cancers that have a high sensitivity to chemotherapy
Lymphomas Germ cell tumour Small cell lung carcinoma Neuroblastoma Wilm’s tumour
Cancers that have a moderate sensitivity to chemotherapy
Breast Bladder Ovary Cervical Colorectal
Cancers that have a low sensitivity to chemotherapy
Prostate
Renal cell carcinoma
Endometrial
Brain tumours
Cytotoxic agents
Antimetabolites - inhibit DNA synthesis
Alkylating agents - act on DNA to impair replication
Intercalating agents - prevent DNA transcription and duplication
Spindle poisons - prevent mitosis
Alkylating agents mechanism of action
- Forms a ligands bond between 2 DNA strands therefore the DNA cannot uncoil for the replication fork when dividing
- Single strand break occurs - cell dies by apoptosis or necrosis
Platinum compounds
Formation of platinated inter and intrastrand adducts (ligand bonds) causing inhibition of DNA synthesis
Intrastrand adducts:
G-G 55%
G-A 31%
Antimetabolite example and mechanism
Methotrexate:
- inhibits dihydrofolate reductase therefore inhibits purine synthesis
5 - fluorouracil
- thymidylate synthase inhibitor
- inhibits purine synthesis
Spindle poisons mechanism of action
Microtubule binding agents
- inhibits polymerisation
- stimulate polymerisation and inhibit depolymerisation
No spindle fibre formation therefore sister chromatids are not separated to opposite poles in anaphase preventing cell replication
Spindle poisoning agent examples
Taxoids:
- promote assembly of tubulin (polymerisation)
- prevents disassembly (depolymerisation)
- cell becomes rigid therefore cannot divide
Vinca alkaloids
- prevent spindle formation
Resistance to alkylating agents
- Tumour cells recognise the alkylating agent and pumps it back out of the cell using a channel
- Decreases the entry or increases the exit of the alkylating agent - Inactivates the alkylating agent as glutathione mops up the active moiety of the agent and neutralises it
- Enhanced repair of DNA lesions produced by alkylation
Chemotherapy use
Used in cancer depending on:
- performance score
- clinical stage of tumour
- prognostic factors
- cytogenetic markers
- side effects vs anticipated best outcome
Chemotherapy routes of administration
IV - common Oral SC - convenient in the community Body cavity - bladder or pleural effusion Intralesional - directly into cancerous area Intrathecal - in CSF Topical IM
IV pump
PICC
- peripherally inserted central catheter
- common but can damage veins in repeated used
Hickman line
- central line to SVC
- prevents infection as increased macrophages near skin
Side effects of chemotherapy
- Nausea and vomiting - directly acts on chemoreceptor trigger zone
- diarrhoea
- bladder cystitis
- sterility
- myalgia
- neuropathy
- alopecia
- pulmonary fibrosis - bleomycin (worse with oxygen) - carry card
- cardiotoxicity - cardiomyopathy and arrhythmia with cyclophosphamide
- renal failure
- myelosuppression
- phlebitis
- mucositis - mouth sores and GI bleeds
ADRs of chemotherapy - due to treatment
Acute renal failure
- hyperuricaemia due to rapid tumour lysis leads to precipitation of urate crystals in renal tubules
GI perforation at site of tumour particularly lymphoma
- peritonitis
- artificial feed to limit damage and better control
DIC
- onset within hours of treatment for acute myeloid leukaemia
Vomiting
Acute phase - 4-12 hours
Delayed phase - 2-5 days
Chronic phase - up to 14 days
Alopecia
Hair thins at 2-3 weeks
Markedly with cyclophosphamide, vinca alkaloids and doxorubicin
Minimal with platinums
Skin toxicity
Local
- irritation and thrombophlebitis of veins
- extravasation (chemotherapy out of vein)
General -bleomycin
- hyperkeratosis
- hyperpigmentation
- ulcerated pressure sores
Hyperpigmentation chemotherapies
Busulphan
Doxorubicin
Cyclophosphamide
Actinomycin D
Chemotherapy dose factors
- BMI
- drug handling i.e. liver or renal function
- comorbidities
Variability of chemotherapy response
Abnormal absorption
- N+ V and gut problems
Abnormal distribution
- weight loss
- ascites
Abnormal excretion
- liver and renal dysfunction
Abnormal protein binding
- low albumin
- drug interactions
Drug interactions
Increase plasma levels of chemotherapy
- vincristine and itraconazole - antifungals that increase neuropathy
- capecitabine (oral 5FU) with warfarin, St John’s Wart and grapefruit juice
- ## methotrexate with penicillin and NSAIDs
Monitoring chemotherapy
- radiological imaging
- tumour marker blood test
- bone marrow/ cytogenetics
- drug assays - for drug level
- check organ damage - eGFR, U+Es, LFTs, echocardiogram
