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Clinical Pharmacology Exam 3 > Pharmacology of anti-cancer drugs > Flashcards

Pharmacology of anti-cancer drugs Flashcards

1
Q

What does cancer treatment depend on?

A
  • Type of cancer
  • Grade
  • Stage
  • Known biological behavior
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2
Q

Grade

A
  • Pathological term
  • Degree of differentiation based on histopathology
  • Mitotic index - # of mitoses seen in 10 HPF (higher = higher likelihood of metastasis)
  • Other marks are often specific for tumor type
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3
Q

AgNor scores

A
  • Mast cell tumor marker
  • Argyrophilic (silver staining) nucleolar organizing regions within individual nuclei
  • Higher score = higher likelihood of metastasis
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4
Q

Tumor staging

A
  • Are metastases present?
  • Looking at the patient
  • Later stage disease means more global therapy
  • What is overall tumor load?
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5
Q

Osteosarcoma behavior

A
  • Thoracic radiographs at time of dx
  • Most have no visible pulmonary metastasis, but 90% of canine osteosarcoma patients will die within 1 year of diagnosis (pulmonary metastases)
  • Must consider treating systemic disease
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6
Q

Other factors considering for cancer tx

A
  • Location (e.g. if in CNS)
  • Oncogenes
  • Receptors
  • MDR1 status
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7
Q

What are the three primary methods of treatment for cancer?

A
  1. Surgery (super important)
  2. Radiation therapy
  3. Systemic disease (some localized tumors): chemotherapy
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8
Q

Treatment of choice for small, localized tumors

A
  • Surgery
  • Any tumor that is low grade, low stage, and cleanly removed
  • Suggests that you don’t need chemotherapy
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9
Q

Idea of selective toxicity of chemotherapy

A
  • Toxic to cancer cells but safe for normal cells
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10
Q

How do cancer treatments accomplish selective toxicity?

A
  • Select for characteristics of cancer cells not shared by normal cells
  • Rapid proliferation
  • Angiogenesis
  • Ability to manipulate immune cells and microenvironment
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11
Q

Rapid proliferation of cancer cells

A
  • MOST cancer cells
  • If chemo is going to be successful, often need to be rapidly proliferating
  • Enzymes, substrates related to: DNA synthesis, DNA structure, and DNA function
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12
Q

Angiogenesis

A
  • Tumors will need to develop their own blood supply in order to survive
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13
Q

What are the 5 stages of the cell cycle?

A
  • M
  • G1
  • G0
  • S
  • G2
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14
Q

How long does mitosis last? What relative proportion of cell cycle (generally) does it take up?

A
  • 1-7 hours
  • Enough to pull the DNA apart
  • Small % of cell cycle
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15
Q

What drug class works during mitosis?

A
  • Vinca alkaloids

- I guess radiation works well here too

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16
Q

How long does G1 last?

A
  • 7-170 hours
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17
Q

What is occurring during G1?

A
  • RNA transcription (mRNA produced)
  • Protein synthesis
  • Proteins required for DNA replication are produced during this phase
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18
Q

What drug class works during G1?

A
  • Not many
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19
Q

What happens during S-phase?

A
  • DNA synthesis in preparation for chromosomal duplication (8-30 hours)
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20
Q

What drug class works during S phase?

A
  • Antimetabolites
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21
Q

How long does G2 last?

A
  • 1-4 hours
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22
Q

What happens during G2?

A
  • Pause prior to mitosis

- Likely to be organization of proteins and cellular machinery required for mitosis

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23
Q

How long does G0 last?

A
  • Can be for years
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24
Q

What happens during G0?

A
  • Cells that aren’t actively cycling (replicating)
  • Neurons, muscle cells do not re-enter cell cycle
  • Hepatocytes normally do not re-enter cell cycle after maturity, but can readily do so
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25
Q

What dictates in which phase of the cell cycle a drug acts?

A
  • Mechanism of action
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26
Q

What is consequence of a drug not being cell cycle specific?

A
  • might kill non-replicating cells as easily as replicating cells
  • Not many anti-cancer drugs are not this category
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27
Q

Cell cycle specific vs phase specific drugs in terms of dosing frequency

A
  • Phase specific you might have to give more often

- Most drugs are cell -cycle specific

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28
Q

What is fractional kill?

A
  • Chemotherapy kills a constant FRACTION of cells, not a constant NUMBER of cells
  • Depending on tumor type and agent involved this can be 10% to 99.9%
  • Nothing will give you 100%
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29
Q

What number of tumor cells is incompatible with human life?

A
  • 1 kg or 10^12 cells

- Not sure

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30
Q

Tumor growth doubling time?

A
  • how long it takes to double population

- Only takes one growth cycle to double

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31
Q

How many doubling times has a 1 g tumor undergone if it started from 1 cell?

A
  • 30 doubling times
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32
Q

How long does it take to get from 10 g (diagnosis) to 1 kg (incompatible with life)?

A
  • Only 10 more doubling times

- Short doubling time is 1 month

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33
Q

How small are the smallest tumors usually that we can detect?

A
  • 1 g

- 1 billion (10^9 cells)

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34
Q

Fractional cell kill charts

A
  • look at them in the notes
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35
Q

What limits chemotherapy dose and interval?

A
  • Host toxicity
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36
Q

What can lead to chemotherapy failure?

A
  • Toxicity to host

- Development of a drug-resistant cell population**

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37
Q

What is a common interval used for chemotherapy drugs?

A
  • Often three week intervals at best

- Allows repopulation of tumor cells

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38
Q

What are chemotherapeutic resistance mechanisms?

A
  1. Altered target
  2. Inactivation of drug
  3. Failure to reach target
  4. Failure to undergo apoptosis (unique to cancer cells)
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39
Q

DNA topoisomerase enzymes

A
  • essential for DNA replication (mammalian form of DNA gyrase)
  • Mutations in enzyme occur in tumor cells to cause resistance
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40
Q

Which mechanism of chemotherapeutic resistance can happen in DNA topoisomerase enzymes to doxorubicin?

A
  • Alteration of the target
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41
Q

Which drug targets DNA topoisomerase enzymes?

A
  • Doxorubicin
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42
Q

Inactivation of drug definition

A
  • Detoxifying mechanisms in normal cells also present in neoplastic cells that can be overexpressed
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43
Q

Example of a drug that is inactivated by some tumors

A
  • Alkylating agents like cyclophosphamide
  • Glutathione-S-transferase system “detoxifies” alkylating agent
  • Tumor cells that over-express glutathione-S-Transferase can be resistant
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44
Q

Which of the chemotherapeutic resistance mechanisms is most important?

A
  • FAILURE TO REACH TARGET
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45
Q

What protein is often implicated in the failure of chemotherapy drugs to reach their target?

A
  • Transport pumps like P-glycoprotein
  • They will pump chemotherapy drugs out of the cell or our of the cell nucleus
  • # 1 cause of MDR
  • Tumors can already have P-glycoprotein (e.g. BBB, hepatocytes, pulmonary parenchyma, or bladders) or develop it
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46
Q

What drugs that we learned about can fail to reach the target as a consequence P-glycoprotein overexpression?

A
  • Doxorubicin
  • Vincristine
  • Vinblastine
  • Taxanes
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47
Q

What is the ultimate method by which each chemotherapeutic agent has been shown to kill cells?

A
  • Inducing apoptosis
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48
Q

What are the two factors that contribute to apoptosis?

A
  • Pro-apoptotic genes

- Anti-apoptotic genes

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49
Q

How can tumors overcome apoptosis?

A
  • Many tumors overexpress bcl-2 (anti-apoptotic)

- Also tumors with mutations in tumor suppressor gene p53 can be resistant to apoptosis

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50
Q

What is a complete response to chemotherapy? (Classic)

A
  • Resolution of clinically apparent disease (e.g. palpable masses, radiographic disease, leukemic cells, paraneoplastic syndromes)
  • For at least one month
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51
Q

Partial response to chemotherapy (Classic)

A
  • Reduction of measurable tumor dimensions by at least 50% for 1 month duration
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52
Q

Stable response to chemotherapy (Classic)

A
  • No change

- <50% reduction in tumor dimensions

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53
Q

Progressive disease response to chemo (Classic)

A
  • Growth of lesion or appearance of new lesions
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54
Q

Resist criteria complete response

A
  • Tumor not detectable
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55
Q

Resist criteria partial response

A
  • Greater than 30% decrease in longest dimension
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56
Q

Resist criteria stable

A
  • Less than 30% decrease or less than 20% of tumor growth
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57
Q

Resist criteria progressive

A
  • greater than 20% of increase in longest dimension observed
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58
Q

Clinical trials overview

A
  • NIH and pharm companies screen hundreds to thousands of synthetic and natural compounds against a panel of tumor cell lines
  • Compounds that show efficacy are tested for toxicity in rodents
  • Those compounds with efficacy and relative safety in rodents may proceed to Phase I clinical trials (only a fraction make it past this hurdle)
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59
Q

Phase I clinical trial (not super important)

A
  • Recruit patients with advanced tumors for which no effective treatment is available
  • Goal to determine max tolerated dose
  • Dose escalation
  • Progress to Phase II if ANY efficacy emonstrated against any tumors
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60
Q

Phase II clinical trial

A
  • Goal to determine which tumor types the drug seems to have efficacy for
  • Recruit patients with advanced tumors of various types
  • More info gained about dosing
  • If activity is demonstrated against a particular tumor type, drug progresses to Phase III
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61
Q

Phase III clinical trial

A
  • Goal to determine if drug candidate and other drugs = improvement over current gold standard
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62
Q

What is the general standard for vet med drugs?

A
  • less rigorously screened and really only need to be “safe”
  • To receive a conditional approval, a drug company must prove, among other things, that the animal drug is safe and has a “reasonable expectation of effectiveness”
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63
Q

What does Body surface area (AKA meter squared) correlate better with?

A
  • Cardiac output
  • Glomerular filtration rate
  • Basal metabolic rate
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64
Q

What does BSA not seem to correlate better with?

A
  • Bone marrow stem cell turnover
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65
Q

BSA of an 8.5 lbs dog

A

0.25 M2

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66
Q

BSA of a 24.5 lb dog

A

0.5 M2

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67
Q

BSA of a 70 lb dog

A

1 M2

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68
Q

BSA of a 128 lb dog

A

1.5 M2

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69
Q

How to calculate BSA in M^2?

A
  • [Km x (W^2/3)]/(10^4)
w= weight in grams 
Km = species factor
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70
Q

What correlates better with myelosuppression: BSA or body weight?

A
  • Body weight
  • Dogs <10 kg more likely to develop myelosuppression if dosed based on BSA as compared to body weight
  • They always say 30 mg/(M^2) unless less than 10 kg
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71
Q

What are the three most common chemotherapy toxicities?

A
  • BAG
  • Bone marrow
  • Alopecia, anaphylaxis, or allergy
  • GI
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72
Q

Infertility and chemo drugs

A
  • It will impact

- need to collect semen before starting chemotherapy

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73
Q

Why do dogs not typically get alopecia on chemo?

A
  • Mostly for rapidly dividing cells (in people, hair cells)

- Dogs have fur not hair

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74
Q

Why do we see bone marrow suppression with chemo?

A

Rapidly dividing cells

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75
Q

Which order are cell lines affected by chemotherapy first?

A
  1. Neutrophils (do a CBC post 1 week getting chemotherapy drug)
  2. Platelets
  3. RBCs (take 120 days; if they drop sooner, worry that we made the cells fragile or have a GI bleed)
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76
Q

Alopecia with chemo drugs in dogs

A
  • Hair follicles are rapidly dividing
  • Dogs and cats don’t have constantly growing hair, but some breeds are more affected (e.g. poodles, old English sheepdogs)
  • Cats may lose whiskers and can become really soft due to losing their guard hairs
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77
Q

Signs of GI toxicity with chemo drugs

A
  • Anorexia, Nausea, vomiting, diarrhea
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78
Q

Relative frequency of GI toxicity in veterinary patients taking chemo drugs

A
  • Less common in veterinary patients than human

- Not sure the cause (dose? Less cerebral input? Metabolic differences?)

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79
Q

Cisplatin mode of nausea

A
  • Directly tells the brain to vomit
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80
Q

Cisplatin how to prevent nausea?

A
  • Premedicate to prevent nausea
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81
Q

Which chemo drugs are most associated with GI toxicity?

A
  • Cisplatin
  • Lomustine
  • Doxorubicin
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82
Q

Lomustine mode of nausea

A
  • Directly tells the brain to vomit
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83
Q

Lomustine how to prevent nausea?

A
  • Give at bedtime to allow sleeping through nausea
  • Vomiting more in dogs than in cats
  • With cats look more for anorexia
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84
Q

Doxorubicin mode of nausea

A
  • Colitis
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85
Q

How to mediate nausea with doxorubicin?

A
  • Fiber or bland diet
86
Q

Infertility and chemo drugs - which sex?

A
  • BOTH males and females
87
Q

Can chemo drugs cause congenital malformations?

A
  • ABSOLUTELY
88
Q

What do you consider when determining a maximum tolerated dose?

A
  • Owner (e.g. owner wants no vomiting or diarrhea)

- Patient (for an MDR1 dog you won’t give the same maximum tolerated dose)

89
Q

Maximum tolerated dose in a patient undergoing palliative care?

A
  • tolerate fewer side effects

- Want to cause no harm whatsoever

90
Q

Maximum tolerated dose in a patient undergoing curative therapy?

A
  • May tolerate greater side effects
91
Q

Three main guidelines of chemotherapy

A
  1. ) DO NOT USE EMPIRICALLY
  2. ) Agent must have efficacy for tumor
  3. ) Monitor with objective criteria
92
Q

Three safety considerations for people handling chemotherapeutic agents (as well as the patients)?

A
  • Carcinogenic
  • Mutagenic
  • Teratogenic
  • Remember that animal waste may contain the active drug
93
Q

Safety considerations for preparing chemo drugs

A
  • Low traffic area
  • Safety hood
  • Gloves
  • Closed systems/chemo pins
  • Always wear gloves!!!!
  • Often need to be double bootied, double gloved, full face shield, and gowned
94
Q

Pill handling chemo drugs

A
  • DO NOT CRUSH UP PILLS
95
Q

MOA of alkylating agents

A
  • Interfere with DNA replication
  • Several mechanisms
    1. ) Alkylates DNA bases. When repair enzymes attempt to repair, they don’t recognize abnormal bases, leading to fragmentation of DNA.
    2. ) Cross bridges form between alkylated bases –> prevention of DNA separation for synthesis or transcription.
    3. ) Mispairing: instead of adenine-thymine and cytosine-guanine, alkylated guanines pair with thymidine lead to mutations. (THIS can lead to toxicity in the patient or owners).
96
Q

Route of alkylating agents

A
  • Oral often

- Very bioavailable

97
Q

Examples of alkylating agents

A
  • Cyclophosphamide
  • Lomustine
  • Chlorambucil
  • Melphalan
98
Q

Nadir for Cyclophosphamide BAG effects

A
  • 7-14 days

- This is the white cell nadir

99
Q

Side effects of cyclophosphamide

A
  • BAG (bone marrow suppression especially

- Sterile hemorrhagic cystitis

100
Q

Sterile hemorrhagic cystitis associated with cyclophosphamide

A
  • Metabolite (acrolein) accumulates in urine
  • Irreversible
  • Prevent by increasing water intake and encouraging frequent voiding (can give prednisone or diuretics)
  • They need to go out every 4 hours 3 times a day
  • Doesn’t matter if low or high dose
101
Q

Lomustine toxicity

A
  • BAG (bone marrow suppression definitely the big one)
  • Chronic neutropenia or thrombocytopenia
  • Hepatic, renal, and lung toxicity long-term
102
Q

When is the nadir for neutropenia or thrombocytopenia with lomustine?

A
  • 1-3 weeks

- Should continue to monitor the white count

103
Q

How to avoid GI toxicity with lomustine?

A
  • Give at night
104
Q

How to prevent or mitigate hepatic, renal, and lung toxicity long-term?

A
  • Monitor chemistries serially

- Dr. Sellon will put on protectants if giving this drug; Dr. Fidel monitors

105
Q

Chlorambucil toxicity

A
  • BAG (less of an issue)

- This is often what they switch to if cyclophosphamide doesn’t work

106
Q

Primary alkylating agent used for lymphoma protocols?

A
  • Cyclophosphamide - 1°
  • Lomustine is a rescue; can penetrate CNS
  • Chlorambucil for low grade lymphomas
107
Q

Which drug typically is used for low grade lymphomas?

A
  • Chlorambucil
108
Q

Which alkylating agent is used for mast cell tumors and histiocytic sarcomas?

A
  • Lomustine
109
Q

Alkylating agents other use

A
  • Component of protocols for a variety of other tumors, e.g. HSA
110
Q

General dosage range with alkylating agents

A
  • Metronomic therapy, given at low constant dose to suppress angiogenesis
  • Sometimes shrinking but more keeping them stable in size
111
Q

General MOA of mitotic inhibitors

A
  • Bind microtubules, thereby interfering with cell division
112
Q

Examples of Mitotic inhibitors

A
  • Vinca alkaloids (Vincristine, Vinblastine)

- Taxanes (Paclitaxel)

113
Q

Toxicity of Vinca alkaloids (mitotic inhibitors)

A
  • BAG
  • Vesicant (one-stick protocol; not so terrible)
  • Neurotoxicity
114
Q

Which vinca alkaloid is more bone marrow suppressive?

A
  • Vinblastine more than vincristine (potentially)
115
Q

Neurotoxicity of vinca alkaloids (mitotic inhibitors)

A
  • This is more FYI
  • NT gets from cell body down to where it needs to get released by traveling via tubules
  • If you interrupt those tubules you don’t get the neurotransmitter
  • Peripheral neuropathy
116
Q

Paclitaxel

A
  • mitotic inhibitor that is not in use anymore
117
Q

Paclitaxel toxicity

A
  • BAG
  • Causes a pretty bad neutropenia
  • Vomiting and anorexia are severe
118
Q

What tumors is vincristine used to treat?

A
  • Lymphoma protocol component

- Transmissible venereal tumor

119
Q

What tumors is vinblastine used to treat?

A
  • Canine mast cell tumor

- Lymphoma

120
Q

WHat tumors is paclitaxel used to treat (or used to be used to treat)?

A
  • Squamous cell carcinoma
  • Mammary tumors
  • Don’t use vincristine or vinblastine for these
121
Q

Route of mitosis inhibitors

A
  • Injectable only
122
Q

Mechanism of cancer “antibiotics”

A
  • Many proposed
    1. INHIBITION OF TOPOISOMERASE is the big one***
    2. Intercalation into DNA
    3. Interfere with DNA as well as RNA synthesis
123
Q

Antitumor antibiotics specificity (e.g. cycling vs phase specific)

A
  • Have to be cycling but not in a specific phase
124
Q

Role of topoisomerase II enzyme complex

A
  • Unwinds DNA for transcription
125
Q

Specific effect of doxorubicin on topoisomerase II

A
  • Stabilizes the DNA in the “broken” or wound DNA configuration
126
Q

Examples of anti-tumor “antibiotics”

A
  • Doxorubicin (Ariamycin)

- Mitoxantrone

127
Q

Toxicity of Antitumor antibiotics (doxorubicin and mitoxantrone)

A
  • BAG (wipe out WBCs)
  • Cumulative cardiac toxicity (Doxorubicin)
  • GI toxicity (colitis)
  • Vesicant
128
Q

When is the nadir for anti-tumor antibiotics and WBCs?

A
  • 7-10 days
129
Q

Cumulative cardiac toxicity of doxorubicin

A
  • Irreversible
  • 180-240 mg/M^2
  • Consider with pre-existing cardiac disease
130
Q

How many doses is typically the max dose for doxorubicin?

A
  • 6 doses generally
131
Q

GI toxicity of doxorubicin - what form of toxicity?

A
  • Colitis (hemorrhagic)
132
Q

Doxorubicin effect on veins

A
  • Vesicant
  • SEVERE tissue reaction is extravasated
  • Can lead to amputation of a limb
  • Do NOT put it on a pump; let it drip
  • “One-stick” per vein
133
Q

Clinical use of antitumor antibiotics (e.g. doxorubicin)

A
  • Lymphoma protocol component
  • Used for sarcomas (best bet)
  • Doxorubicin has high activity against a variety of tumors
134
Q

Relative cardiotoxicity and efficacy of newer antitumor antibiotic analogs

A
  • Less cardiotoxic

- Also less efficacious

135
Q

Bleomycin

A
  • Antitumor antibiotic used for electrochemotherapy
136
Q

MOA of platinum compounds

A
  • Intra-strand cross-link of DNA interfering with RNA synthesis and DNA replication
137
Q

Examples of platinum compounds

A
  • Cisplatin

- Carboplatin

138
Q

Relative dosing of cisplatin and carboplatin

A
  • Cisplatin has MUCH MUCH lower dosing than carboplatin
139
Q

Which of the platinum compounds tends to be used more?

A
  • Carboplatin
140
Q

Cisplatin toxicity with BAG

A
  • BAG
  • HIGHLY HIGHLY emetogenic
  • Patients require anti-emetics, always pre-treatment
141
Q

BAG Toxicity of Carboplatin

A
  • BAG
  • Less emetogenic than cisplatin
  • Bimodal nadir of carboplatin at 6 and 15 days
142
Q

Monitoring CBC with carboplatin

A
  • Due to bimodal nadir of carboplatin, check at 1, 2, and 3 weeks
143
Q

Relative nephrotoxicity of carboplatin and cisplatin

A
  • Cisplatin has high nephrotoxicity

- Diuresis pre, during, and post treatment

144
Q

Respiratory toxicity of cisplatin vs carboplatin

A
  • Fatal pulmonary edema in cats

- Carboplatin is much safer in cats

145
Q

General toxicities of cisplatin and carboplatin rehash :)

A
  1. BAG
  2. Nephrotoxicity
  3. Lung toxicity
  4. Ototoxicity
146
Q

Cisplatin and carboplatin tumor types

A
  • Cisplatin was agent of choice for osteosarcoma but largely replaced by carboplatin
  • Carcinomas
  • Intralesional in equine sarcoids with beads
147
Q

Antimetabolites MOA

A
  • Interfere with purine and pyrimidine synthesis and incorporation into DNA
148
Q

Examples of anti-metabolites

A
  • Methotrexate
  • Cytosine arabinoside
  • 5-fluorouracil (5-FU)
  • Azathiprine
149
Q

Toxicity of Methotrexate (antimetabolite)

A
  • BAG

- NAdir around 1 week

150
Q

Drug interaction potential with methotrexate

A
  • highly protein bound - drug interaction potential
151
Q

General length of action of antimetabolites

A
  • Most are phase specific

- Short acting

152
Q

5- fluorouracil toxicity (antimetabolite)

A
  • BAG (white count)

- Central neurotoxicity (fatal in cats)

153
Q

Aazthioprine toxicity

A
  • BAG (lower frequency in dogs than other agents)

- Avoid in cats (myelosuppression)

154
Q

Cytosine arabinoside toxicity

A
  • BAG nadir 1-14 days
155
Q

Tumor type for methotrexate

A
  • Component of older protocol for lymphoma

- Not used that often anymore

156
Q

Tumor type for 5-fluorouracil (5-FU)

A
  • Carcinomas
157
Q

Clinical use for azathioprine

A
  • Immune mediated diseases
158
Q

Clinical use for cytosine arabinoside

A
  • Lymphoma in horses (arabinoside for Arabian horses)
  • Canine non-infectious encephalitis
  • Acute leukemia
159
Q

Mechanism of action of enzymes like L-asparaginase

A
  • Inhibits protein synthesis

- Depriving tumor of asparagine

160
Q

Example of anti-tumor enzyme

A
  • L-asparaginase
161
Q

Toxicity of enzymes like L-asparaginase

A
  • Allergic reactions
  • Relatively bone marrow sparing (unless in combination with vincristine)
  • Pancreatitis
  • Sometimes vomiting
162
Q

What to do with a patient vomiting on L-asparaginase?

A
  • Take more seriously than you might with other drugs

- Could be pancreatitis

163
Q

What history might preclude use of enzymes like L-asparaginase?

A
  • Pancreatitis
164
Q

What to do for prevention of allergic reactions with L-asparaginase?

A
  • Pretreat with antihistamines +/- glucocorticoids
165
Q

Clinical use of L-asparaginase

A
  • Lymphoma
166
Q

Route of L-asparaginase

A
  • SC only

- NOT IV (anaphylaxis risk)

167
Q

Mechanism of NSAIDs for use with tumors

A
  • COX-2 overexpressed in many tumors
  • May be a growth factor?
  • NSAIDs enhance apoptosis
  • Decrease tumor invasiveness
  • Block angiogenesis
168
Q

Piroxicam

A
  • NSAID
  • They used to use this
  • Not COX-2 selective, so more chance for GI ulceration
169
Q

Toxicity of piroxicam

A
  • GI ulceration

- renal

170
Q

Tumors to treat with piroxicam or other NSAIDs (deracoxib)

A
  • Transitional cell carcinoma

- Palliation of other tumor types

171
Q

What might be a better NSAID and why for treating transitiona cell carcinoma in dogs?

A
  • Deracoxib
  • COX-2 selective, so less likely to cause ulceration
  • Same chance of renal injury
172
Q

Tyrosine kinase inhibitors MOA

A
  • Inhibit cell signaling (proteins involved in cell replication)
173
Q

Examples of tyrosine kinase inhibitors

A
  • Toceranib phosphate (Palladia)
174
Q

Indication for Toceranib phosphate

A
  • 1st FDA approved drug for treating cancer in veterinary patients
  • Grade II and III mast cell tumors
175
Q

Route for tyrosine kinase inhibitors

A
  • Tablets
176
Q

What drug should you avoid with tyrosine kinase inhibitors?

A
  • NSAIDs

- VERY protein bound, which will change the metabolism of NSAIDs

177
Q

Masitinib drug type

A
  • Tyrosine kinase inhibitors
178
Q

Masitinib use in the US

A
  • Currently off market in US
  • Was indicated for grade II and III mast cell tumors
  • similar to toceranib
179
Q

Adverse effects of Tyrosine Kinase inhibitors (Toceranib)

A
  • Neutropenia (Check CBCs once a week)
  • GI ulceration (Avoid NSAIDs)
  • Vasculitis (thromboembolic disease)
  • Protein losing nephropathy
180
Q

How long do animals stay on tyrosine kinase inhibitors?

A
  • For life

- making cancer behave

181
Q

MOA of Canine Melanoma vaccine

A
  • DNA vaccine
  • Human tyrosinase
  • Tyrosinase is present on the surface of melanoma cells
  • Triggers immune response
182
Q

Approval of Canine Melanoma vaccine

A
  • USDA approved
  • Stage II or III melanoma in conjunction with standard treatment (surgery or radiation therapy) for local disease
  • Proprietary injection device
183
Q

Dosing protocol for ONCEPT or the canine melanoma vaccine

A
  • 2 weeks apart + 6 month booster
184
Q

Why are the results for the ONCEPT/Canine melanoma vaccine so equivocal?

A
  • Initial efficacy study compared to historical controls
185
Q

Adverse effects of ONCEPT/canine melanoma vaccine

A
  • Injection site pain
  • Fever
  • Hypersensitivity (rare)
  • Localized vitiligo
186
Q

Cons of the canine melanoma vaccine

A
  • Expensive
  • At least two studies done recently showed that Stage II and Stage III didn’t have a difference in progression-free survival
  • Other therapies might be better now
187
Q

Pros of canine melanoma vaccine

A
  • Pretty safe

- Might work for some dogs

188
Q

Definition of metronomics

A
  • Low doses more frequency to cut down on some negative side effects
189
Q

Metronomics - which drugs used with metronomics?

A
  • Alkylating agents

- Oral

190
Q

Benefits of metronomics?

A
  • Cuts down on negative effects

- may have anti-angiogenic effects

191
Q

Metronomic lomustine study

A
  • discontinued because of toxicity

- GI, liver toxicity, azotemia, thrombocytopenia, neutropenia, etc.

192
Q

Metronomic cyclophosphamide toxicity

A
  • Greater incidence of cystitis potentially

- Did seem to make it past median return time for tumors in combo with piroxicam

193
Q

How to manage nausea/vomiting in patients on anticancer drugs?

A
  • Maropitant (Cerenia)
  • Ondansetron
  • Butorphanol (specifically prior to cisplatin)
194
Q

Which anti-cancer drug can lead to diarrhea?

A
  • Doxorubicin
195
Q

Doxorubicin diarrhea - what to do?

A
  • She thinks it’s a result of giving them a lot of cookies
  • If you give a controlled diet, that might help control
  • Loperamide (MUST KNOW MDR1 status)
  • Morphine
  • Metronidazole
  • Imodium or a high fiber diet
196
Q

What therapies can be given to dogs who experience diarrhea on anticancer drugs?

A
  • Morphine (particularly dogs that are painful from severe tenesmus)
  • Metronidazole (due to bacterial overgrowth)
  • Also could try high fiber diet or imodium (loperamide
197
Q

GI complications secondary to mast cell tumors

A
  • Excess histamine
198
Q

Treatment for GI complications secondary to mast cell tumors

A
  • Prevent GI ulceration with H2 blockers (famotidine or ranitidine)
  • PPI (omeprazole)
199
Q

Managing neutropenia

A
  • Treatment depends on grade and presence of fever
200
Q

Treatment for grade 1-2 neutropenia (afebrile)

A
  • oral antibacterial agent
  • Selection based on most likely source of infection
  • Some people might not put them on antibiotics and tell the owner to monitor temperature
201
Q

Grade 3-4 neutropenia (afebrile) in cancer patient

A
  • Oral antibacterial agents (Clavamox or cephalexin)

- 4 quadrant coverage

202
Q

Patient with any degree of neutropenia who is febrile?

A
  • Parenteral or injectable medications

- Might be septic

203
Q

rhG-CSF usage

A
  • Most effective if given PRIOR to treatment with cytotoxic
  • I think it’s an antibody thing
  • Antibody production (rhG-CSF) can cause prolonged CSF
204
Q

How long to keep a neutropenic cancer patient in the hospital for?

A
  • NO LONGER THAN WHAT IS NECESSARY
  • Keep them until their temperature goes down and they take oral medications
  • Don’t wait until WBC increases, as it’s dangerous for them to be in hospital
205
Q

Which chemo treatments are substrates for P-glycoprotein?

A
  • Vincristine and vinblastine
  • Doxorubicin (antibiotics)
  • Paclitaxel
206
Q

What side effects are more likely in dogs with MDR1 mutation?

A
  • Bone marrow suppression
  • Thrombocytopenia
  • GI
  • Neuropathy
207
Q

Are dogs with MDR1 heterozygote mutation capable of being sensitive to chemotherapeutic drugs?

A
  • YES
208
Q

Why are dogs with MDR1 sensitive to chemotherapeutic drugs?

A
  • Not a blood-brain-barrier problems
  • More like P-gp is needed for biliary excretion of vincristine, vinblastine, doxorubicin, and paclitaxel
  • They will circulate longer
209
Q

Clinical implications for treating dogs with cancer with possible MDR1

A
  • Test ALL herding breeds
  • Test mixed breed dogs
  • MDR1 mutant/mutant dogs have SEVERE adverse effects
210
Q

Dose reductions for an MDR1 mutant/mutant?

A
  • 50% decrease
211
Q

MDR1 reductions for an MDR1 heterozygote?

A
  • 25%

Clinical Pharmacology Exam 3 (5 decks)

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