Chemotherapy Flashcards
What is the mechanism of action of the alkylating agents?
binding of alkyl groups to cellular macromolecules to generate inter or intra-strand crosslinks
Which chemotherapy agents are akylators?
Nitrogen mustards: Mechlorethamine, melphalan, cyclophosphamide, ifosfamide, chlorambucil
Nitrosureas: Lomustine, streptozotocin
Other: dacarbazine, procarbazine
What is the specific mechanism of action of mustargen?
spontaneous hydrolysis –> nucleophilic reactive centers that form DNA crosslinks (i.e. a bifunctional alkylator)
What is a mechanism of resistance to mustargen based on its clinical pharmacology?
Carrier mediated uptake into cells, decreased uptake = resistance
How do you treat mustargen extravasation?
Sodium thiosulfate 2.5% administered through the catheter before it is removed or injected directly into the site at the same volume as mustargen
What is the dose and ROA of mustargen?
3 mg/m2 IV
What is the clinical use of mustargen?
Lymphoma
Does melphalan require metabolic activation?
No - direct alkylating activity
What can block uptake of melphalan and why?
Leucine - melphalan actively transported into cells through amino acid transporters
What is the primary toxicity of melphalan?
Neutropenia and thrombocytopenia
What is the clinical use of melphalan?
Multiple myeloma
What is the dose, ROA, and frequency of administration of melphalan?
0.1 mg/kg PO induction x 14d, then 0.05 mg/kg PO q24h
Alternate for dogs: 7 mg/m2 PO q24h x5d every 3 weeks OR 2 mg/m2 PO q24h x10d then 10d off and repeat
What organ activates cyclophosphamide and how?
Liver – microsomal mixed function oxidases through ring oxidation –> spontaneous and reversible ring opening –> irreversible breakdown
What are the two breakdown products of cyclophosphamide and which is the active compound?
Phosphoramide mustard (active) and acrolein
What is the major dose limiting toxicity of cyclophosphamide?
Neutropenia
What does acrolein cause and how do we mitigate it?
Sterile hemorrhagic cystitis, more common with chronic oral dosing
Treat with furosemide 1-2 mg/kg PO or IV to minimize risk
Mesna to bind
Which neoplasias can we treat with cyclophosphamide and what kind of dosing?
Lymphoma - bolus dosing
Sarcoma and mammary carcinoma - fractionated or metronomic
What is the bolus dosing and ROA of cyclophospamide?
200 - 250 mg/m2 PO or IV
What dose of cyclophosphamide is used for bone marrow ablation?
500 - 750 mg/m2 IV
What is the fractionated dosing and ROA for cyclophosphamide (dog)?
50 - 75 mg/m2 PO for 3-4 consecutive days
Like cyclophosphamide, which other drug requires microsomal mixed function activation in the liver to form an active compound capable of bifunctional alkylation?
Ifosfamide
What is the metabolite produced in the body from ifosfamide and what potential toxicity can it cause?
chloracetaldehyde, neurotoxicity
What are three potential dose limiting toxicities of ifosfamide?
myelosuppresion, nephrotoxicity, damage to the bladder epithelium, neurotoxicity?
What drug must be administered with ifosfamide to avoid severe cystitis?
Mesna
What is the clinical indication of ifosfamide?
treatment of sarcomas
What is the recommended dose of ifosfamide in dogs and cats?
Dogs - 375 mg/m2 IV every 3 weeks
Cats - 900 mg/m2 IV every 3 weeks
*must have saline diuresis
How does chlorambucil enter cancer cells?
Passive diffusion
Which organ is primarily responsible for chlorambucil metabolism?
Liver
What are the major dose limiting toxicities of chlorambucil?
Myelosuppression - granulocytopenia and thrombocytopenia
What are the clinical indications of chlorambucil?
CLL, replace cyclophosphamide in CHOP, Waldenstroms macroglobulinemia, feline small cell lymphoma, metronomic therapy for TCC
What is the dose and ROA for dogs and cats on chlorambucil?
3 to 6 mg/m2 PO q24h
4 mg/m2/d in dogs
2 mg EOD or MWF in cats
20 mg/m2 every 2 weeks in cats
How is lomustine taken into cancer cells?
Passive diffusion - lipid soluble
How is CCNU activated?
spontaneously decomposes to a reactive center to cause DNA-alkylation, DNA-DNA and DNA-protein cross-links at physiologic pH
What is one of the unique features of CCNU as a product of its lipophilicity?
Crosses the blood-brain barrier
Which organ is responsible for lomustine metabolism?
Liver
What are the major dose limiting toxicities of CCNU?
Neutropenia
Cumulative, irreversible thrombocytopenia
Hepatic enzyme elevations and dysfunction (ALT)
Pulmonary fibrosis in cats – rare
When is the nadir of CCNU in cats?
1 to 4 weeks post treatment
What is a medication that can reduce the risk of ALT elevation with CCNU administration?
Denamarin
What is the clinical indication for CCNU in dogs?
Canine lymphoma, MCT, histiocytic sarcoma
What is the clinical indication for CCNU in cats?
lymphoproliferative disorders, MCT
What is the dose of CCNU in dogs? Cats?
Dogs - 70 - 90 mg/m2 PO q3wks
Cats - 40 - 60 mg/m2 PO q4-6 wks or 10 mg/cat q4-6 wks
How does streptozotocin enter cancer cells?
Dependent on GLUT2 transporter uptake
What is the clinical indication of streptozotocin?
Insulinoma
What is the dose and ROA of streptozotocin?
500 mg/m2 IV infusion with saline diuresis every 2 weeks
How is dacarbazine metabolically activated?
Hepatic cytochrome p450
In which species is dacarbazine not recommended and why?
Cats - can’t convert parent drug to prodrug
In which organ is dacarbazine metabolized and excreted?
Metabolized - liver
Excreted - kidneys
What is the major dose limiting toxicity of dacarbazine?
GI toxicity
What is the clinical indication for dacarbazine?
lymphoproliferative diseases in relapse setting, heamngiosarcoma (+ dox, +/- vinc)
What is the dose of dacarbazine single agent? In multi-agent protocols?
Single - 800 - 1000 mg/m2 IV q3wks
Combo - 600 - 800 mg/m2 IV or infusion 200 mg/m2/d IV for 5 days
What unique organ of interest can procarbazine affect?
CNS - rapidly equilibrates with CSF
What is the clinical indication of procarbazine?
treatment of lymphoma in combo with mustargen/CCNU/vinc/pred, hemangiosarcoma
What is the dosing and ROA of procarbazine?
50 mg/m2/d PO q24h x 14d
*no IV administration b/c CNS toxicity with IV dosing
What are tyrosine kinase inhibitors?
Small molecule inhibitors that block receptor tyrosine kinases (RTKs) expressed on the cell surface by competitively inhibiting ATP binding
What are the three TKIs that have been used most commonly in veterinary oncology?
Palladia (toceranib phosphate), masitinib, and imatinib mesylate (Gleevec)
What are the primary targets of Palladia?
CD117 (KIT), VEGFR2 (vascular endothelial growth factor receptor 2), PDGFRB (platelet-derived growth factor receptor B), Flt-3 (FMS-like tyrosine kinase-3)
Which human TKI is toceranib phosophate most similar to?
Sunitinib
What are the primary targets of imatinib?
KIT, Abl, PDGFR
Where is palladia primarily excreted?
Feces (90%)
Only 10% in urine
Mechanisms of neoplastic cell inhibition of Palladia?
Antiangiogenic - inhibit VEGFR and PDGFR on endothelial cells and pericytes
Directly inhibit normal or mutated RTKs which promote cell division and survival
What are the most common adverse events of treatment with Palladia?
diarrhea, vomiting, hyporexia, and GI bleeding (less common)
What are less common but concerning side effects of palladia?
Hypertension, PLN (dogs)
What is a side effect in the TKIs specific to imatinib?
indiosyncratic hepatotoxicity
What is the labeled dose for Palladia?
3.25 mg/kg PO q48h
What is the dosing (dogs) for Palladia that has been shown effective and better tolerated than the label dose?
2.5 - 2.75 mg/kg PO q48h or MWF
What are the clinical indications of Palladia?
Canine MCT
Activity against: AGASACA, GIST, thyroid carcinoma, nasal adenocarcinoma
What is the dosing recommendation for cats receiving Palladia and for what neoplastic condition?
Condition: MCT
Dose: 2.7 mg/kg per M/W/F
What is the recommended dosing and ROA for imatinib?
10 mg/kg PO q24h
- Small number of patients
- Most treated <1 month
Why is mg/kg used for cats and dogs less than 15kg with doxorubicin?
Evidence shows better toxicity profile when mg/kg used
Which class of drugs are antimicrotubule agents?
Taxanes and Vinca alkaloids
Mechanism of action Taxanes
Stabilize microtubules against depolymerization leading to mitotic arrest
Clinically used taxanes
Paclitaxel and Docetaxel
Excretion of taxanes?
Hepatic metabolism and biliary excretion
Cause of hypersensitivity associated with Taxanes?
hypersensitivity secondary to cremophor EL (paclitaxel) and polysorbate 80 (docetaxel)
Dose limiting toxicity of Taxanes?
Diarrhea and neutropenia
Is hypersensitivity more manageable in docetaxel or paclitaxel?
Docetaxel
What drugs are in the vinca alkaloid group?
Vincristine, Vinblastine, Vindesine, and vinorelbine
Mechanism of action of vinca alkaloids?
Bind to tubulin and inhibit microtubule assembly resulting in metaphase arrest and cytotoxicity
How do vinca alkaloids enter cells?
Diffusion
How are vinca alkaloids primarily excreted?
Hepatic metabolism and biliary excretion. Only 10-20% renal excretion
Vincristine side effects?
Myelosupression, peripheral neurotoxicity, GI effects, and Ileus
Is vincristine or vinblastine more myelosuppressive?
Vinblastine
Treatment for vincristine extravasation?
5-10mL saline infused around affected area (+/- hyaluronidase), warm compresses, and a topical solution of DMSO, flucinolone acetonide (Synotic), and flunixin meglumine after each warm compress
Vincristine uses?
Lymphoma, TVT
Vincristine dose?
0.5 - 0.75mg/m2 IV bolus weekly
Vinblastine uses?
MCT, canine bladder TCC, rescue for lymphoma, or in place of vincristine in multi-agent protocols to minimize GI AEs
Vinblastine dose?
Dogs:
Weekly - 2.0 - 3 mg/m2
EOW - 3.0 - 3.5 mg/m2
Cats:
1.5mg/m2 in COP based protocol
Vinorelbine uses?
Primary lung tumors, histiocytic sarcoma, MCTs
Vinorelbine dose?
Dogs: 15mg/m2
Cats: 11.5mg/m2
Topoisomerase inhibitor classes?
Anthracyclines and epipodophyllotoxins
Clinically relevant epipodophyllotoxins?
Etoposide and teniposide
Epipodophyllotoxins mechanism of action?
Inhibit catalytic activity of topoisomerase II by stabilizing protein-DNA cleavage complex leading to single and double stranded DNA breaks
How do epipodophyllotoxins enter cells?
Diffusion
Major toxicity of etopiside? and why?
Severe histamine release in dogs after IV administration. This is due to polysorbate 80 vehicle
How is etopiside metabolized and eliminated?
hepatic metabolism and renal elimination of parent drug and metabolites
Dose limiting toxicity of etoposide?
hypersensitivity
Etoposide uses?
None due to hyperactivity with IV administration and low bioavailability of oral administration
Mechanism of action Prednisone/Prednisolone?
Killing hematopoietic cancer through interaction with glucocorticoid receptor and induction of apoptosis (still not completely understood)
Prednisone uses?
lymphoid malignancies, MCT, insulinoma, brain tumors in dogs and cats
MOA of platinum agents?
Covalent binding to DNA through displacement reactions resulting in bifunctional lesions and inter- or intrastrand crosslinks
Metabolism carboplatin/cisplatin?
Reactions with water and elimination by binding plasma and tissue proteins; primarily excreted in urine
Dose limiting toxicity cisplatin?
Nausea and vomiting and renal; vigorous saline diuresis and antiemetics needed
Why is cisplatin contraindicated in cats?
Fatal pulmonary vasculitis and edema
Dose limiting toxicity carboplatin?
Myelosuppression
Clinical use cisplatin?
Primarily OSA; also TCC, mesothelioma, carcinomatosis, germinal cell tumors
Dose cisplatin?
50-70mg/m2 IV administration with saline diuresis and antiemetics q3 weeks
Carboplatin uses dogs?
OSA, AGASACA, SCC, intestinal carcinoma, prostatic carcinoma, mesothelioma, carcinomatosis; inferior to cisplatin for TCC
Dose of carboplatin?
Dogs: 300mg/m2 or 10mg/kg IV q3weeks
Cats:200 to 240mg/m2 q3weeks (can use GFR and AUC)
Carboplatin uses cats?
injection site sarcoma, HSA, colonic adenocarcinoma, oral SCC
Hydroxyurea mechanism of action?
Inhibitor of ribonucleotide reductase resulting in depletion of deoxyribonucleotide pools
Adverse effects hydroxyurea?
GI, myelosuppression, rarely pulmonary fibrosis
Onycholysis in dogs with chronic use
Use of hydroxyurea?
Polycythemia vera, granulocytic leukemias, MCT
Dosage hydroxyurea?
50-60mg/kg q24hr x 2 weeks, then decrease to 30mg/kg/d to lessen myelosuppressive and onycholytic effects
Mechanism of action L-asparaginase?
Hydrolysis of L-asparagine to L-aspartic acid leads to inhibition of protein synthesis in tumor cells which lack L-asparagine synthetase causing apoptosis
Adverse effects L-asparaginase?
hypersensitivity, decreasing effectiveness
Drug class of Doxorubicin
Antitumor Antibiotic (anthracycline)
Doxorubicin mechanism of action (hint: 8 answers)
Multimodal:
1. DNA intercalation
2. Inhibition of RNA/DNA polymerases
3. Inhibition of DNA topoisomerase II
4. Alkylation of DNA
5. ROS species generation
6. Pertubation of cellular calcium homeostasis
7. Inhibition of thioredoxin reductase
8. Interaction with plasma membrane components
Doxorubicin metabolism (mechanism, metabolite, and elimination)
Mechanism: Liver metabolism to via side chain reduction via aldo-keto reductases and 7-hydroxy aglycone (primarily liver but also extrahepatic tissues)
Metabolite: Doxorubicinol
Elimination: Renal and biliary
Drug class of Mitoxantrone
Antitumor antibiotic (synthetic Dox analogue)
Mitoxantrone mechanism of action
Same as Dox but oxidative damage and less potential to create ROS
Mitoxantrone metabolism
Extensively distributed throughout tissues. Not extensively metabolized and 30% of drug is excreted unchanged in urine and feces.
Actinomycin Deez nuts - mechanism of action and how does it get into the cell
Binds to single and double stranded DNA and results in inhibition of transcription (thus RNA and protein synthesis inhibition)
Important: Enters cell by passive diffusion and sensitivity depends on cell uptake and retention.
ABCB1 involved in drug efflux out of cells
Actinomycin D metabolism
Rapidly distributed to tissues with minimal metabolism. 20% excreted unchanged in urine and feces
What is an antimetabolite drug?
inhibits the use of cellular metabolites in cell growth and division (i.e. generally analogs of compounds in normal metabolism)
Cytarabine (Cytosine Arabinoside; Ara-C) - MOA and analog
Analog of Deoxycytidine and is phosphorylated in cells to generate ara-CTP (a competitive inhibitor of DNA polymerase alpha and integrates itself into DNA). Actively taken up into cells via nucleoside transporters
Hugely important: S Phase Specific
Cytarabine metabolism
Distributes in total body water and crosses BBB (CSF levels reaching 60% of plasma levels)
Primary mode of metabolism is deamination via the liver.
Methotrexate - MOA and analog
Folate analog
Inhibits dihydrofolate reductase (thus depleting folate required for purine and thymidylate synthesis)
Active transport into cells via reduced folate carrier
Methotrexate metabolism
Undergoes enterohepatic recycling (accounts for GI side effects at the doses that do not cause BM toxicity). Only undergoes hepatic metabolism at high dosages and is primarily excreted unchanged in urine.
Gemcitabine MOA
Actively transported into cells via nucleoside transporters. Inhibits DNA synthesis via DNA polymerase inhibition, inhibition of ribonucleotide reductase, and subsequent depletion of ribonucleotide pools and incorporation into DNA
5-FU (Fluorouracil) MOA and Analog
analog of uracil
Converted to active nucleotide forms intracellulary and incorporated into DNA and RNA
IMPORTANT: S-phase specific
5-FU metabolite
FdUMP (Fluorodeoxyuridylate) is an active metabolite that inhibits thymidylate synthetase
Can I give 5-FU to a cat?
Of course! But the cat will die of neurotoxicity sooo….
Tanovea MOA and Analog
Tanovea is a multistep activated pro-drug that results in intracellular generation of the nucleotide analog PMEG [9-(2-phosphonylmethoxyethyl)guanine]
- Produced via hydrolysis
- Competes as a substrate for DNA polymerases and incorporates itself into DNA
Tanovea Metabolism
Studies have shown preferred uptake in PBMCs and lymphoid tissue
Has selective metabolism in liver and kidney via dealkylation
What does the ATP-binding cassette (ABC) do?
Involved in drug efflux from cells (ATP-dependent transport of substrates)
Name veterinary cancers that express ABC transporters
ABCB1 expression in canine lymphoma
canine mammary tumors
canine and feline primary pulmonary carcinoma
What is the general, primary method of multidrug resistance in veterinary oncology?
Induction of drug efflux pumps
