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Chemotherapy Flashcards

1
Q

What is the mechanism of action of the alkylating agents?

A

binding of alkyl groups to cellular macromolecules to generate inter or intra-strand crosslinks

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2
Q

Which chemotherapy agents are akylators?

A

Nitrogen mustards: Mechlorethamine, melphalan, cyclophosphamide, ifosfamide, chlorambucil

Nitrosureas: Lomustine, streptozotocin

Other: dacarbazine, procarbazine

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3
Q

What is the specific mechanism of action of mustargen?

A

spontaneous hydrolysis –> nucleophilic reactive centers that form DNA crosslinks (i.e. a bifunctional alkylator)

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4
Q

What is a mechanism of resistance to mustargen based on its clinical pharmacology?

A

Carrier mediated uptake into cells, decreased uptake = resistance

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5
Q

How do you treat mustargen extravasation?

A

Sodium thiosulfate 2.5% administered through the catheter before it is removed or injected directly into the site at the same volume as mustargen

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5
Q

What is the dose and ROA of mustargen?

A

3 mg/m2 IV

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5
Q

What is the clinical use of mustargen?

A

Lymphoma

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6
Q

Does melphalan require metabolic activation?

A

No - direct alkylating activity

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7
Q

What can block uptake of melphalan and why?

A

Leucine - melphalan actively transported into cells through amino acid transporters

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8
Q

What is the primary toxicity of melphalan?

A

Neutropenia and thrombocytopenia

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9
Q

What is the clinical use of melphalan?

A

Multiple myeloma

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10
Q

What is the dose, ROA, and frequency of administration of melphalan?

A

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

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11
Q

What organ activates cyclophosphamide and how?

A

Liver – microsomal mixed function oxidases through ring oxidation –> spontaneous and reversible ring opening –> irreversible breakdown

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12
Q

What are the two breakdown products of cyclophosphamide and which is the active compound?

A

Phosphoramide mustard (active) and acrolein

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13
Q

What is the major dose limiting toxicity of cyclophosphamide?

A

Neutropenia

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14
Q

What does acrolein cause and how do we mitigate it?

A

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

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15
Q

Which neoplasias can we treat with cyclophosphamide and what kind of dosing?

A

Lymphoma - bolus dosing
Sarcoma and mammary carcinoma - fractionated or metronomic

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16
Q

What is the bolus dosing and ROA of cyclophospamide?

A

200 - 250 mg/m2 PO or IV

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17
Q

What dose of cyclophosphamide is used for bone marrow ablation?

A

500 - 750 mg/m2 IV

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18
Q

What is the fractionated dosing and ROA for cyclophosphamide (dog)?

A

50 - 75 mg/m2 PO for 3-4 consecutive days

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19
Q

Like cyclophosphamide, which other drug requires microsomal mixed function activation in the liver to form an active compound capable of bifunctional alkylation?

A

Ifosfamide

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20
Q

What is the metabolite produced in the body from ifosfamide and what potential toxicity can it cause?

A

chloracetaldehyde, neurotoxicity

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21
Q

What are three potential dose limiting toxicities of ifosfamide?

A

myelosuppresion, nephrotoxicity, damage to the bladder epithelium, neurotoxicity?

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22
Q

What drug must be administered with ifosfamide to avoid severe cystitis?

A

Mesna

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23
Q

What is the clinical indication of ifosfamide?

A

treatment of sarcomas

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24
Q

What is the recommended dose of ifosfamide in dogs and cats?

A

Dogs - 375 mg/m2 IV every 3 weeks
Cats - 900 mg/m2 IV every 3 weeks

*must have saline diuresis

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25
Q

How does chlorambucil enter cancer cells?

A

Passive diffusion

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26
Q

Which organ is primarily responsible for chlorambucil metabolism?

A

Liver

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27
Q

What are the major dose limiting toxicities of chlorambucil?

A

Myelosuppression - granulocytopenia and thrombocytopenia

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28
Q

What are the clinical indications of chlorambucil?

A

CLL, replace cyclophosphamide in CHOP, Waldenstroms macroglobulinemia, feline small cell lymphoma, metronomic therapy for TCC

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29
Q

What is the dose and ROA for dogs and cats on chlorambucil?

A

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

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30
Q

How is lomustine taken into cancer cells?

A

Passive diffusion - lipid soluble

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31
Q

How is CCNU activated?

A

spontaneously decomposes to a reactive center to cause DNA-alkylation, DNA-DNA and DNA-protein cross-links at physiologic pH

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32
Q

What is one of the unique features of CCNU as a product of its lipophilicity?

A

Crosses the blood-brain barrier

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33
Q

Which organ is responsible for lomustine metabolism?

A

Liver

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34
Q

What are the major dose limiting toxicities of CCNU?

A

Neutropenia
Cumulative, irreversible thrombocytopenia
Hepatic enzyme elevations and dysfunction (ALT)
Pulmonary fibrosis in cats – rare

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35
Q

When is the nadir of CCNU in cats?

A

1 to 4 weeks post treatment

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36
Q

What is a medication that can reduce the risk of ALT elevation with CCNU administration?

A

Denamarin

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37
Q

What is the clinical indication for CCNU in dogs?

A

Canine lymphoma, MCT, histiocytic sarcoma

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38
Q

What is the clinical indication for CCNU in cats?

A

lymphoproliferative disorders, MCT

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39
Q

What is the dose of CCNU in dogs? Cats?

A

Dogs - 70 - 90 mg/m2 PO q3wks
Cats - 40 - 60 mg/m2 PO q4-6 wks or 10 mg/cat q4-6 wks

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40
Q

How does streptozotocin enter cancer cells?

A

Dependent on GLUT2 transporter uptake

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41
Q

What is the clinical indication of streptozotocin?

A

Insulinoma

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42
Q

What is the dose and ROA of streptozotocin?

A

500 mg/m2 IV infusion with saline diuresis every 2 weeks

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43
Q

How is dacarbazine metabolically activated?

A

Hepatic cytochrome p450

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44
Q

In which species is dacarbazine not recommended and why?

A

Cats - can’t convert parent drug to prodrug

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45
Q

In which organ is dacarbazine metabolized and excreted?

A

Metabolized - liver
Excreted - kidneys

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46
Q

What is the major dose limiting toxicity of dacarbazine?

A

GI toxicity

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47
Q

What is the clinical indication for dacarbazine?

A

lymphoproliferative diseases in relapse setting, heamngiosarcoma (+ dox, +/- vinc)

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48
Q

What is the dose of dacarbazine single agent? In multi-agent protocols?

A

Single - 800 - 1000 mg/m2 IV q3wks
Combo - 600 - 800 mg/m2 IV or infusion 200 mg/m2/d IV for 5 days

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49
Q

What unique organ of interest can procarbazine affect?

A

CNS - rapidly equilibrates with CSF

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50
Q

What is the clinical indication of procarbazine?

A

treatment of lymphoma in combo with mustargen/CCNU/vinc/pred, hemangiosarcoma

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51
Q

What is the dosing and ROA of procarbazine?

A

50 mg/m2/d PO q24h x 14d
*no IV administration b/c CNS toxicity with IV dosing

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52
Q

What are tyrosine kinase inhibitors?

A

Small molecule inhibitors that block receptor tyrosine kinases (RTKs) expressed on the cell surface by competitively inhibiting ATP binding

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53
Q

What are the three TKIs that have been used most commonly in veterinary oncology?

A

Palladia (toceranib phosphate), masitinib, and imatinib mesylate (Gleevec)

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54
Q

What are the primary targets of Palladia?

A

CD117 (KIT), VEGFR2 (vascular endothelial growth factor receptor 2), PDGFRB (platelet-derived growth factor receptor B), Flt-3 (FMS-like tyrosine kinase-3)

55
Q

Which human TKI is toceranib phosophate most similar to?

A

Sunitinib

56
Q

What are the primary targets of imatinib?

A

KIT, Abl, PDGFR

57
Q

Where is palladia primarily excreted?

A

Feces (90%)
Only 10% in urine

58
Q

Mechanisms of neoplastic cell inhibition of Palladia?

A

Antiangiogenic - inhibit VEGFR and PDGFR on endothelial cells and pericytes

Directly inhibit normal or mutated RTKs which promote cell division and survival

59
Q

What are the most common adverse events of treatment with Palladia?

A

diarrhea, vomiting, hyporexia, and GI bleeding (less common)

60
Q

What are less common but concerning side effects of palladia?

A

Hypertension, PLN (dogs)

61
Q

What is a side effect in the TKIs specific to imatinib?

A

indiosyncratic hepatotoxicity

62
Q

What is the labeled dose for Palladia?

A

3.25 mg/kg PO q48h

63
Q

What is the dosing (dogs) for Palladia that has been shown effective and better tolerated than the label dose?

A

2.5 - 2.75 mg/kg PO q48h or MWF

64
Q

What are the clinical indications of Palladia?

A

Canine MCT
Activity against: AGASACA, GIST, thyroid carcinoma, nasal adenocarcinoma

65
Q

What is the dosing recommendation for cats receiving Palladia and for what neoplastic condition?

A

Condition: MCT
Dose: 2.7 mg/kg per M/W/F

66
Q

What is the recommended dosing and ROA for imatinib?

A

10 mg/kg PO q24h
- Small number of patients
- Most treated <1 month

67
Q

Why is mg/kg used for cats and dogs less than 15kg with doxorubicin?

A

Evidence shows better toxicity profile when mg/kg used

68
Q

Which class of drugs are antimicrotubule agents?

A

Taxanes and Vinca alkaloids

69
Q

Mechanism of action Taxanes

A

Stabilize microtubules against depolymerization leading to mitotic arrest

70
Q

Clinically used taxanes

A

Paclitaxel and Docetaxel

71
Q

Excretion of taxanes?

A

Hepatic metabolism and biliary excretion

72
Q

Cause of hypersensitivity associated with Taxanes?

A

hypersensitivity secondary to cremophor EL (paclitaxel) and polysorbate 80 (docetaxel)

73
Q

Dose limiting toxicity of Taxanes?

A

Diarrhea and neutropenia

74
Q

Is hypersensitivity more manageable in docetaxel or paclitaxel?

A

Docetaxel

75
Q

What drugs are in the vinca alkaloid group?

A

Vincristine, Vinblastine, Vindesine, and vinorelbine

76
Q

Mechanism of action of vinca alkaloids?

A

Bind to tubulin and inhibit microtubule assembly resulting in metaphase arrest and cytotoxicity

77
Q

How do vinca alkaloids enter cells?

A

Diffusion

78
Q

How are vinca alkaloids primarily excreted?

A

Hepatic metabolism and biliary excretion. Only 10-20% renal excretion

79
Q

Vincristine side effects?

A

Myelosupression, peripheral neurotoxicity, GI effects, and Ileus

80
Q

Is vincristine or vinblastine more myelosuppressive?

A

Vinblastine

81
Q

Treatment for vincristine extravasation?

A

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

82
Q

Vincristine uses?

A

Lymphoma, TVT

83
Q

Vincristine dose?

A

0.5 - 0.75mg/m2 IV bolus weekly

84
Q

Vinblastine uses?

A

MCT, canine bladder TCC, rescue for lymphoma, or in place of vincristine in multi-agent protocols to minimize GI AEs

85
Q

Vinblastine dose?

A

Dogs:
Weekly - 2.0 - 3 mg/m2
EOW - 3.0 - 3.5 mg/m2

Cats:
1.5mg/m2 in COP based protocol

86
Q

Vinorelbine uses?

A

Primary lung tumors, histiocytic sarcoma, MCTs

87
Q

Vinorelbine dose?

A

Dogs: 15mg/m2
Cats: 11.5mg/m2

88
Q

Topoisomerase inhibitor classes?

A

Anthracyclines and epipodophyllotoxins

89
Q

Clinically relevant epipodophyllotoxins?

A

Etoposide and teniposide

90
Q

Epipodophyllotoxins mechanism of action?

A

Inhibit catalytic activity of topoisomerase II by stabilizing protein-DNA cleavage complex leading to single and double stranded DNA breaks

91
Q

How do epipodophyllotoxins enter cells?

A

Diffusion

92
Q

Major toxicity of etopiside? and why?

A

Severe histamine release in dogs after IV administration. This is due to polysorbate 80 vehicle

93
Q

How is etopiside eliminated?

A

hepatic metabolism and renal elimination of parent drug and metabolites

94
Q

Dose limiting toxicity of etoposide?

A

hypersensitivity

95
Q

Etoposide uses?

A

None due to hyperactivity with IV administration and low bioavailability of oral administration

96
Q

Mechanism of action Prednisone/Prednisolone?

A

Killing hematopoietic cancer through interaction with glucocorticoid receptor and induction of apoptosis (still not completely understood)

97
Q

Prednisone uses?

A

lymphoid malignancies, MCT, insulinoma, brain tumors in dogs and cats

98
Q

MOA of platinum agents?

A

Covalent binding to DNA through displacement reactions resulting in bifunctional lesions and inter- or intrastrand crosslinks

99
Q

Metabolism carboplatin/cisplatin?

A

Reactions with water and elimination by binding plasma and tissue proteins; primarily excreted in urine

100
Q

Dose limiting toxicity cisplatin?

A

Nausea and vomiting and renal; vigorous saline diuresis and antiemetics needed

101
Q

Why is cisplatin contraindicated in cats?

A

Fatal pulmonary vasculitis and edema

102
Q

Dose limiting toxicity carboplatin?

A

Myelosuppression

103
Q

Clinical use cisplatin?

A

Primarily OSA; also TCC, mesothelioma, carcinomatosis, germinal cell tumors

104
Q

Dose cisplatin?

A

50-70mg/m2 IV administration with saline diuresis and antiemetics q3 weeks

105
Q

Carboplatin uses dogs?

A

OSA, AGASACA, SCC, intestinal carcinoma, prostatic carcinoma, mesothelioma, carcinomatosis; inferior to cisplatin for TCC

106
Q

Dose of carboplatin?

A

Dogs: 300mg/m2 or 10mg/kg IV q3weeks
Cats:200 to 240mg/m2 q3weeks (can use GFR and AUC)

107
Q

Carboplatin uses cats?

A

injection site sarcoma, HSA, colonic adenocarcinoma, oral SCC

108
Q

Hydroxyurea mechanism of action?

A

Inhibitor of ribonucleotide reductase resulting in depletion of deoxyribonucleotide pools

109
Q

Adverse effects hydroxyurea?

A

GI, myelosuppression, rarely pulmonary fibrosis
Onycholysis in dogs with chronic use

110
Q

Use of hydroxyurea?

A

Polycythemia vera, granulocytic leukemias, MCT

111
Q

Dosage hydroxyurea?

A

50-60mg/kg q24hr x 2 weeks, then decrease to 30mg/kg/d to lessen myelosuppressive and onycholytic effects

112
Q

Mechanism of action L-asparaginase?

A

Hydrolysis of L-asparagine to L-aspartic acid leads to inhibition of protein synthesis in tumor cells which lack L-asparagine synthetase causing apoptosis

113
Q

Adverse effects L-asparaginase?

A

hypersensitivity, decreasing effectiveness

114
Q

Drug class of Doxorubicin

A

Antitumor Antibiotic (anthracycline)

115
Q

Doxorubicin mechanism of action (hint: 8 answers)

A

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

116
Q

Doxorubicin metabolism (mechanism, metabolite, and elimination)

A

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

117
Q

Drug class of Mitoxantrone

A

Antitumor antibiotic (synthetic Dox analogue)

118
Q

Mitoxantrone mechanism of action

A

Same as Dox but oxidative damage and less potential to create ROS

119
Q

Mitoxantrone metabolism

A

Extensively distributed throughout tissues. Not extensively metabolized and 30% of drug is excreted unchanged in urine and feces.

120
Q

Actinomycin Deez nuts - mechanism of action and how does it get into the cell

A

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

121
Q

Actinomycin D metabolism

A

Rapidly distributed to tissues with minimal metabolism. 20% excreted unchanged in urine and feces

122
Q

What is an antimetabolite drug?

A

inhibits the use of cellular metabolites in cell growth and division (i.e. generally analogs of compounds in normal metabolism)

123
Q

Cytarabine (Cytosine Arabinoside; Ara-C) - MOA and analog

A

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

124
Q

Cytarabine metabolism

A

Distributes in total body water and crosses BBB (CSF levels reaching 60% of plasma levels)
Primary mode of metabolism is deamination via the liver.

125
Q

Methotrexate - MOA and analog

A

Folate analog
Inhibits dihydrofolate reductase (thus depleting folate required for purine and thymidylate synthesis)
Active transport into cells via reduced folate carrier

126
Q

Methotrexate metabolism

A

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.

127
Q

Gemcitabine MOA

A

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

128
Q

5-FU (Fluorouracil) MOA and Analog

A

analog of uracil
Converted to active nucleotide forms intracellulary and incorporated into DNA and RNA
IMPORTANT: S-phase specific

129
Q

5-FU metabolite

A

FdUMP (Fluorodeoxyuridylate) is an active metabolite that inhibits thymidylate synthetase

130
Q

Can I give 5-FU to a cat?

A

Of course! But the cat will die of neurotoxicity sooo….

131
Q

Tanovea MOA and Analog

A

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

132
Q

Tanovea Metabolism

A

Studies have shown preferred uptake in PBMCs and lymphoid tissue
Has selective metabolism in liver and kidney via dealkylation

133
Q

What does the ATP-binding cassette (ABC) do?

A

Involved in drug efflux from cells (ATP-dependent transport of substrates)

134
Q

Name veterinary cancers that express ABC transporters

A

ABCB1 expression in canine lymphoma
canine mammary tumors
canine and feline primary pulmonary carcinoma

135
Q

What is the general, primary method of multidrug resistance in veterinary oncology?

A

Induction of drug efflux pumps

136
Q
A

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