Antineoplastic Drugs Flashcards
What is the MOA of alkylating agents?
They transfer an alkyl group to the DNA of rapidly proliferating cells and disrupt the process leading to cell destruction
What drug classes fall under alkylating agents and related drugs? (3)
Nitrosoureas
Nitrogen mustards
Platinum coordination complexes
Discuss the pharmacokinetic factors of alkylating agents and related drugs regarding cell phase.
Phase-nonspecific, dose-dependent
What are the 4 main side effects of alkylating agents and related drugs?
Emetogenic
Vesicant
Mutagenic (rare)
Myelosuppressive (often dose-limiting)
Name 3 nitrosoureas.
Carmustine
Lomustine
Semustine
Name 2 nitrogen mustards.
Cyclophosphamide
Ifosfamide
Which alkylating drug class consists of prodrugs that require hydroxylation by CYP450? Which drug is activated more slowly?
Nitrogen mustards; ifosfamide is activated more slowly than cyclophosphamide
What is the highly toxic compound formed during the activation of nitrogen mustards?
Acrolein
What can acrolein cause?
Hemorragic cystitis/renal damage
How can you circumvent the toxic effects of acrolein?
Aggressive IV hydration
Using Mesna, a drug which forms a complex with acrolein and inactivates it
What are the major AEs of nitrogen mustard toxicity? (4)
Emetogenic
Myelosuppression
Alopecia
Mucosal ulcerations (dose-limiting)
Name 3 platinum coordination complexes.
Cisplatin, carboplatin, and oxaliplatin
What are the major toxicities of platinum coordination complexes?
RENAL
OTOTOXICITY
Profound nausea and vomiting/anticipatory
Electrolyte disturbances (HYPOMAGNESEMIA)
Describe the pharmacokinetics of platinum coordination complexes.
Highly protein bound (cisplatin) RENAL EXCRETION (AND ACCUMULATION WHICH CAN LEAD TO TOXICITY) Large VD (Oxaliplatin - long duration of action)
Why is cisplatin still used if it has a higher SE profile than oxaliplatin?
Very effective against certain cancers
Name the cell cycle-specific drug classes.
Antimetabolites
Natural Products - Vinca Alkaloids, Taxanes, Anthracycline Antibiotics
Name an antimetabolite.
Methotrexate
What is the MOA of methotrexate?
INHIBITS DIHYDROFOLATE REDUCTASE which is required for the synthesis of normal DNA/RNA bases. MTX inhibits dTMP (thymidine monophosphate) synthesis which then inhibits DNA synthesis.
MTX interferes with the _______ cycle in the human body, contributing to toxicity. Therefore, __________ is given as “rescue” therapy.
folate; leucovorin
What is leucovorin?
Fully reduced folate
What are 2 significant mechanisms of resistance against MTX?
MUTATED DHFR WHICH HAS DECREASED AFFINITY FOR MTX
GENE AMPLIFICATION OF DHFR
What AE of MTX is usually dose-limiting?
Mucosal ulcerations/GI toxicity
What pharmacokinetic property of MTX can lead to a major toxicity as well as a major DDI?
90% renal excretion - renal toxicity and DDI with NSAIDs which decrease the excretion of MTX through decreased RBF and GFR
Name 3 natural products (plant alkaloids) that have the same mechanism of resistance.
Vinca Alkaloids (flower) Taxanes (yew bark) Anthracycline Abx (fungus)
Mech is P-glycoprotein inducement
Name 4 vinca alkaloids.
Vincristine, vinblastine, vindesine, vinorelbine
What is the MOA of vinca alkaloids?
Bind to tubulin and prevent polymerization of microtubules; CCS for M phase.
Considering the MOA of vinca alkaloids, what is the major toxicity of concern?
Motor neuron and central neurotoxicity since microtubules are important for axonal integrity and transport.
What is the major mechanism of resistance for vinca alkaloids?
P-glycoprotein
What is the MOA of taxanes?
Alter microtubules through uncontrolled polymerization; work primarily in M-phase of cell cycle
Due to MOA, what is the major toxicity caused by taxanes?
Peripheral neuropathy because of abnormal microtubules
Name 2 taxanes.
Paclitaxel, docetaxel
Why do taxanes sometimes cause a hypersensitivity reaction upon infusion?
Ethanol/castor oil vehicle used due to limited solubility
How can you pretreat against a taxane infusion reaction?
Dexamethasone and antihistamines
What are 2 mechanisms of resistance for taxanes?
P-glycoprotein
Mutated tubulin
Name 5 anthracycline antibiotics.
DOXORUBICIN
Daunorubicin, valrubicin, epirubicin, idarubicin
Name the MOAs of anthracycline antibiotics (3).
DNA intercalator (insert between 2 strands/prevent unwinding)
Inhibit topoisomerase II (prevents unwinding and clipping of DNA)
Generation of reactive oxygen species (leading to apoptosis of cancer cells)
What are the mechanisms of resistance for anthracyclines? (3)
P-glycoprotein
Mutations in Topo II
Increased activity of glutathione peroxidase (decreases ROS)
What is the major toxicity of concern for anthracyclines and why?
Cardiotoxicity; associated with doses greater than 550 mg/m2. Probably due to the generation of ROS. May cause CHF unresponsive to digoxin therapy!
How can you prevent cardiotoxicity caused by anthracyclines?
Treat patient with iron-chelating agent dexrazoxane!
What can occur up to 6 months after treatment with anthracyclines after implementing another cancer therapy?
Radiation recall reaction
What is a drug with a different toxicity profile and MOA from other antineoplastic agent making it ideal for combination regimens?
Bleomycin
Describe the MOA of bleomycin.
Molecule contains a DNA-binding region and an iron-binding domain at opposite ends. Forms a complex with iron and “shunts” electrons from iron to molecular oxygen, forming ROS that destroy the DNA.
What enzyme prevents bleomycin toxicity in the liver, spleen, and bone marrow?
Bleomycin hydrolase which inactivates bleomycin (can also be a mechanism of resistance in tumor cells)
Where is bleomycin hydrolase NOT present in the body, resulting in concerns for toxicity?
Skin and lungs
What are the major toxicities of concern with bleomycin?
Cutaneous and pulmonary toxicity
What an important anesthesia implication with recent bleomycin therapy?
Run low FiO2s to prevent ROS/pulmonary toxicity
What is the mechanism of resistance with bleomycin?
Increased hydrolase activity
