Cancer Chemotherapy Flashcards
What are the advantages of molecular targeting approaches? Give an example
Rationally designed targets & inhibitors
Tumour selective
More efficacious
Fewer side effects
More selective
E.g. Imatinib (ST1571, Glivec) Bcr-Abl tyrosine kinase inhibitor
Which stage of the cell cycle does chemo/ radiotherapy not work? What can be done to prevent this stopping treatment from working?
G0
Can give some drugs which aim to keep cells in the cycle & out of G0
What is the fractional cell kill hypothesis?
A defined chemotherapy concentration applied for a defined time period will kill a constant fraction of the cells in a population, independent of the absolute number of cells.
So it’s used to calculate how often to give chemotherapy - time chemo when bone marrow cells have recovered but tumour cells are not back to original concentration
List the main cytotoxic chemotherapeutic groups
Antimetabolites
Alkylation agents
Intercalating agents
Mitotic inhibitors (spindle poisons)
How do alkylation agents work? Give an example
Alkylation agents impair replication through single or double strand DNA breaks -> apoptosis
E.g. platinum compounds (Oxaliplatin, cisplatin, carboplatin)
Formation plants aged inter & intrastrand aDducts -> inhibits DnA synthesis
How do antimetabolites work? Give an example
Interfere with 1+ enzymes/ reactions necessary for DNA synthesis by acting as a substitute to the actual metabolites
E.g. 5- flurouracil inhibits thymidylate synthase (used in the synthesis of DNA & the folate cycle)
Methotrexate inhibits dihydrofolate reductase (in folate cycle)
How do spindle poisons work?
Aka mitotic inhibitors
Normally: Chromosomes align at metaphase plate -> spindle microtubules depolymerise, moving sister chromatids towards opposite poles -> nuclear membrane re-forms & cytoplasm divides
Microtubule- binding agents disrupt microtubule dynamics: inhibit polymerisation e.g. vinca alkaloids OR stimulate polymerisation & prevent depolymerisation e.g. taxoids
Mechanisms of resistance to alkylation agents
Decreased entry or exit of agent e.g. through pumps
Inactivation of agent in cell e.g. glutathione neutralises alkylation agents
Enhanced repair of DNA lesions produced by alkylation
How do intercalating agents work?
Inhibit DnA replication -> insert between bases & change DnA strand e.g. lengthening/ twisting
How is the predicted response of chemotherapy calculated within the same cancer for different patients?
Based on: Performance score (0=best)
Clinical stage of tumour
Prognostic factors or score (often involving biological factors)
Molecular or cytogenetic markers
Weigh up side effects with anticipated/ best outcome
How is chemotherapy usually administered?
For many cancers chemotherapy regimen will consist of a number of different drugs - combination chemotherapy - usually given as an acronym but a drug may be given as a single agent
Routes:
IV - most common (bolus/ infusional bag/ continuous pump - PICC vein arm or Hickman line in chest)
PO
SC (in community setting)
Into a body cavity - bladder/ pleural effusion
Intralesional - directly into cancerous area
Intrathecal - into CSF (lumbar puncture/ Omaya reservoir)
Topical - on the skin
IM - rarely
List some side effects of chemotherapy (10)
Acute renal failure - hyperuricaemia (lysis tumour cells) -> precipitation urate crystals in renal tubules
GI perforation at site of tumour -> peritonitis (lymphoma)
Disseminated intravascular coagulopathy (myeloid leukaemia)
Vomiting - central chemoreceptor trigger zone (acute 4-12hrs, delayed onset 2-5days, chronic phase -14days)
Alopecia - hair thins 2-3weeks, May total, may re-grow during therapy, can prevent scalp cooling
Skin toxicity - local (thrombophlebitis/ irritation/ extravasation), general (bleomycin/ hyperkeratosis/ hyperpigmentation/ ulcerated pressure sores), hyperpigmentation
Mucositis - GI tract epithelium damage, sore mouth/ throat/ diarrhoea/ GI bleed
Cardio- toxicity - cardio-myopathy mortality 50%, arrhythmias particularly alkylation agents
Lung toxicity - bleomycin (pul fibrosis) worse with O2 carry cards for life
Haematological toxicity - most frequent dose limiting, most frequent cause of toxic death, neutropenia/ thrombocytopenia
What needs to be taken into account when considering dosing & treatment phasing?
Dosing: Surface area BMI Drug handling ability General well-being
Treatment phasing: Growth fraction Cell kill of each cycle Marrow & GI recovery Tolerability of regimen
Dangerous drugs - marrow therapeutic indices, significant side effect profile
What cause variability in pharmacokinetics?
Absorption - N&V, compliance, gut problems
Distribution - weight loss, reduced body fat, ascites
Elimination - liver & renal dysfunction, other meds
Protein binding - low albumin, other drugs, poor nutrition
Important drug interactions
Other drugs may increase plasma levels:
- vincristine & itraconazole (antifungal) -> more neuropathy
- capecitabine & warfarin
- methotrexate caution with prescribing penicillin/ NSAIDs
- capecitabine & St Johns Wort (supplement), grapefruit juice
