Chemotherapy Flashcards
Alkylating agents: Examples, MOA, Cell cycle phase, Resistance Mechanisms
- Cyclophosphomide, CCNU, Streptozosin, Melphalan, Chlorambucil, Procarbazine
- Alkylate DNA (+/- RNA) strands causing strand breaks and in some cases strand cross links.
- Phase non-specific
- Reduced uptake, increased efflux, upregulation of enzymes removing DNA methylation or improved DNA repair
Antitumour Antibiotics: Examples, MOA, Cell cycle phase, Resistance Mechanisms
- Doxorubicin, Mitoxantrone, Epirubicin, Actinomycin D
- Inhibition of topoisomerases; generation of ROS; DNA/RNA/protein synthesis inhibition
- Cell cycle phase non-specific
- Increased drug efflux, increased expression of GTS enzymes to enhance detoxification in cells, increased topoisomerase activity
Vinca Alkaloid Antimicrotubule Drugs:
Examples, MOA, Cell cycle phase, Resistance Mechanisms
- Vincristine, Vinblastine
- bind to B-tubulin and prevent polymerisation for spindle formation
- Cell cycle M phase specific
- Apoptosis inhibition, B-tubulin binding site mutation
Taxan Antimicrotubule:
Examples, MOA, Cell cycle phase, Resistance Mechanisms
- Paclitaxel, Docetaxal
- suppress spindle microtubule dynamics, preventing breakdown
- Cell cycle M phase specific (Telophase)
Tyrosine Kinase inhibitors:
Examples, MOA, Cell cycle phase, Resistance Mechanisms
- toceranib, masitinib
- prevents ATP binding to the phosphorylation site and thus activation of VEGF, KIT and PDGF receptors. All involved in angiogenesis
- May also inhibit Treg function
- Cell cycle phase G1/2 specific
- Increased P-gp efflux expression; changes to receptor binding site/reduced expression of receptor.
Platinum Compounds: Examples, MOA, Cell cycle phase, Resistance Mechanisms
- Carboplatin, Cisplatin
- inorganic molecule that is activated intracellularly and becomes charged resulting in covalent binding to DNA and creation of cross-links. Impairing DNA replication, RNA synthesis and thus protein synthesiss.
- Cell cycle phase non-specific
- reduced transport into cells, increased tiourea production to inactivate compound, increased efflux or enhanced DNA repair.
Anti-metabolites:
Examples, MOA, Cell cycle phase, Resistance Mechanisms
- Methotrexate (folate analogue that binds to enzyme in its place and thus limiting DNA synthesis)
- Cytarabine (converted to active compound intracellularly then inhibits DNA synthesis. Also incorporated in to DNA).
- Gemcitibine (incorporated into DNA strands)
- All active in G1 and S phase
L-asparaginase:
MOA, Cell cycle phase, Resistance Mechanisms
- Converts L-asparagine to aspartic acid limiting cell supply of the former (not needed in normal cells but cancer cells often lose ability to synthesise this de novo).
- Cell cycle phase G1 specific
- Production of L-asparagine synthetase, reduction in asparagine efflux, increased utilisation of L-glutamine through L-glutaminase and increased glutamine uptake.
Mechanisms of Chemoresistance
- Drug inactivation (CYP, GTS) - critical for doxo resistance
- Apoptosis downregulation (BCL2 gene expression blocks normal pathways to apoptosis)
- Drug efflux - ABCB1 and other P-gp. pump out hydrophobic substances
- Target Modification - reduced expression, increased expression of inhibitor, altered drug target
- Altered DNA repair - loss or downregulation of p53
Features of Cancer Stem Cells
- similar to normal stem cells, induced by IL-8
- enhanced DNA repair and resistance to apoptosis
- Multiple mechanisms of chemoresistance expressed
- Quiescent so resistant to many chemotherapies
Chemotherapy Myelosuppression - VCOG 2020 neut grades guidelines, when to postpone chemo.
Neuts and plt primarily affected due to short half life and rapid bone marrow transit times
- clinical status is of high importance in evaluation
- Grade 1 <1.5; 2 1-1.5; 3 0.5-1; 4 <0.5
- ABx recommended if grade 3 or higher or if systemic signs such as fever or lethargy
- JVIM 2018 reported no increase in incidence of adverse effects if cut off for additional chemo reduced to 1.5 - and this minimised delays
Myelosuppression - VCO 2018 ABx prophylaxis recommendations and subsequent studies on cut off
- Empirical cut off of <1 (grade 3 or higher) or if febrile/unwell
- could also recommend empirical prophylaxis if high risk patient (sml dog, lymphoma, intensive protocol, MDR1 mutation risk)
- VCO 2020 trial used cut off of 0.75 to give empirical ABX and this was well tolerated. Though incidence of febrile neutropaenia was low overall.
- ABx choice in humans is fluoroquinolone but TMS may also be approrpriate
Grading of GI chemotoxicity
1 mild and <48h duration
2 requiring outpatient treatment and resolves in 48-72h
3. moderate to severe requiring hospitalisation or >3d treatment
4. life threatening (ie sepsis criteria)
Chemotherapy cardiotoxicity:
Cause
Recent publications (2)
Cumulative oxidative injury to cardiac myocytes resulting in cardiomyopathy.
- Risk is increased in breeds with pre-existing genetic susceptibility - JVIM 2019 showed 15% prevalence compared to 3% in gen pop.
- JVIM 2020 showed cTN1 increased only after Tx cycle finished but was predictive of echo changes consistent with DCM
Metronomic Chemotherapy MOA
- Antiangiogenesis - inhibit vasculogenesis indirectly, directly inhibit VEGF stimulated endothelial growth
- Immunomodulatory - inhibit or kill Treg cells and TAMS/MDSC.
- Induction of dormancy - increased cell death/reduced proliferation result in a cell cycle equilibirum. Or cell cycle arrest occurs.
- Kill Cancer Stem cells through anti-angiogenic effects
