CPTP3.7: Anti-cancer drugs Flashcards
What is the general mechanism of cytotoxic drugs?
They interfere with DNA replication, generally causing cell apoptosis.
What are the main classes of cytotoxic drugs? Give the drug name of each.
- Alkylating agents - CYCLOPHOSPHAMIDE
- Anthracyclines - DOXORUBICIN
- Antimetabolites - METHOTREXATE
- Tubulin binders - VINCRISTINE
- Protein kinase inhibitors - IMATINIB
How does CYCLOPHOSPHAMIDE work (alkylating agent)? Describe its mechanism.
Induction of DNA double strand breaks -> inhibition of DNA replication
It has a reactive -CL group which reacts with DNA, cross-linking them -> causing double strand break at replication fork -> DNA can no longer be replicated
What are some side effects of CYCLOPHOSPHAMIDE?
Key side effect: Bone marrow suppression (neutropenia)
Anaemia and thrombocytopenia handled with blood/platelets tranfusion
Produces toxic metabolite that can cause cystitis (inflammation of bladder)
How does DOXORUBICIN (topoisomerase I/II inhibitors) work? Describe its mechanism.
It’s an anthracycline antitumour antibiotic - most commonly used chemotherapy agent to stabilise DNA double strand breaks
Less common alias: ADRIAMYCIN
As topoisomerases are essential for DNA replication
What are some side effects of DOXORUBICIN?
Similar side effect profile to CYCLOPHOSPHOMIDE
Common side effect: mucositis (mouth full of ulcers)
Heart scan required to detect cardiac failure due to its cardiotoxicity
How does METHOTREXATE (antimetabolites) work? Describe its mechanism
Inhibition of purine and pyrimidine (building blocks) synthesis -> inhibition of DNA replication [Main mode of action of antimetabolites]
Inhibits key enzymes particularly the DHFR (dihydrofolate reductase) which are involved in thymidylate synthesis / building block formation -> DNA cells can’t properly form
What supplement is given to patients that are given METHOTREXATE?
Folinic acid.
It is an antidote to the toxic effects of METHOTREXATE on normal cells as patients with e.g. osteosarcoma are subjected to high doses of METHOTREXATE for 24 hours and then are prescribed folinic acid to save ‘normal’ cells.
How is METHOTREXATE given to patients?
Given in addition with other drugs (VINCRISTINE and 6-mercaptopurine)
Also given intrathecally as BBB prevents this drug from reaching the brain and patients can die due to meningeal leukemia due to cancer cells surviving at brain region.
What are some side effects of METHOTREXARE?
Similar side effect profile to CYCLOPHOSPHAMIDE.
Key side effect: Mucositis
Kidney function is always checked as if it isn’t excreted properly, crystals can be formed which will further impair renal function -> inability to excrete METHOTREXATE -> toxicity
Can also cause skin rash.
How does VINCRISTINE (tubulin binders) work? Describe its mechanism and how is it different from other cytotoxic drugs?
It inhibits separation of chromosomes in mitosis via binding to tubulin -> inhibits mitosis -> antiproliferative effects
What are some side effects of VINCRISTINE?
Side effects differ from other cytotoxic agents
Most common side effect and key problem: neuropathic pain
Avoid extravasation -> cannot be given into peripheral tissues as it causes severe tissue damage -> should only be administered intravenously
Can VINCRISTINE be administered via CNS? I.e. intrathecally
NO. It is lethal if given as intrathecal injection.
Highly regulated in the U.K.
What is the therapeutic index/ratio for cancer chemotherapy agents like? How so?
Very low, the drugs are used at or near the maximum tolerated dose as they’re toxic to normal proliferating tissue (bone marrow/GI tract/hair follicles)
How does IMATINIB (protein kinase inhibitors) work? Describe its mechanism.
A mutation leading to the fusion of BCR and ABL genes -> BCR-ABL protein which will constantly cause the cell to proliferate -> IMATINIB binds to this abnormal protein instead of ATP (ATP blocker/competitor) to inactivate BCR-ABL
