Chemotherapy Flashcards
Alkylating-like agents: Cisplatin
Examples: cisplatin, carboplatin, oxaliplatin, cyclophosphamide
Bind to purine bases on DNA and form inter- and intra-crosslinks
Block DNA and protein synthesis - G2 arrest
Nephrotoxicity - cisplatin is eliminated by the kidney so it can accumulate here - can be controlled by diuretics and pre-hydration
Hepatotoxicity - cisplatin increases CYP450 levels, causing oxidative stress - antioxidants selenium and vitamin E reduce this
Gastrointestinal toxicity - increased nausea and vomiting
Antimetabolites: Methotrexate
Examples: Methotrexate, 5-fluorouracil, gemcitabine, mercaptopurine
Folic acid transports carbon for methylation and nucleic acid synthesis.
Methotrexate is an analogue - binds dihydrofolate reductase (DHFR), competitively inhibiting the conversion of dihydrofolate to tetrahydrofolate, which is essential for purine synthesis
Inhibits DNA, RNA, and protein synthesis,
Nephrotoxicity - precipitates in tubules and causes crystal nephropathy → increased serum creatine and tubular necrosis
Hepatic fibrosis and increased risk of cirrhosis
Pulmonary effects - fever, dry cough, chest pain - less common but potentially fatal
Mucositis - damage to the mucosal barrier increases risk of infection - can be rate-limiting
Neurotoxicity - demyelinating encephalopathy with dementia, motor paralysis, seizures, aphasia and stroke symptoms
Topoisomerase I inhibitors: Topotecan
Topoisomerase I regulates DNA supercoiling by causing single strand breaks and re-ligation
Topotecan interferes with this by intercalating with DNA bases
Short half-life limits efficacy
Myelosuppression - neutropenia and thrombocytopenia → increased risk of infection, bruising, anaemia
Other side-effects: allergic reactions, nausea and vomiting
Topoisomerase II inhibitors: Doxorubicin
Topoisomerase II regulate supercoiling, causing cleavage of both DNA strands
Doxorubicin is part of the anthracycline antibiotic family of cytotoxic agents.
Binds to the DNA duplex by intercalating C-G sequences.
Generates free radicals and binds to membranes to alter fluidity and ion transport.
Cardiotoxicity - dilative cardiomyopathy and congestive heart failure due to disrupted sarcomere structure with myofilament disorganisation in cardiomyocytes.
Sarcomeric synthesis is disrupted due to genotoxic stress, mitochondrial dysfunction and oxidative stress.
Microtubule poisons: Vincristine
Also called antineoplastics
Bind tubulin and prevent polymerisation into microtubules, blocking the M phase of the cell cycle.
Vincristine is combined with the glucocorticoid prednisone for the treatment of ALL.
Neuropathy - peripheral damage: paraesthesia, neuropathic pain, motor nerve damage
Neurotoxicity causes autonomic dysfunction → orthostatic hypotension
Gastrointestinal effects - nausea and vomiting, constipation, abdominal cramps
