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Pharmacology II > LEC 27,28 - Anti-Neoplastics > Flashcards

LEC 27,28 - Anti-Neoplastics Flashcards

1
Q

What replicative phase do most mature animals enter?

A

G0 - will then reactivate with injury

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2
Q

What cells in the body have constant replication?

A

Skin/hair follicles, GI epithelium, Bone marrow, and male gametes

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3
Q

What is the normal progression through the cell cycle regulated by?

A

Presence of growth signals and check points

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4
Q

What are the six replication check points?

A

G1 to S, during S phase, during G2 (DNA damage and replication checkpoint), Antephase checkpoint, and spindle assembly checkpoint

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5
Q

What happens in the spindle checkpoint.

A

Make sure that things are seperating correctly

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6
Q

What happens in the antephase checkpoint?

A

Check the environment (ie. presence of ROS) to make sure conditions are okay for replication

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7
Q

What happens in the DNA checkpoint in the middle of the S phase?

A

Proofread the daughter cell for DNA mistake

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8
Q

Where are the two most common places that cancer cells have mutations in?

A

Oncogenes or tumor suppressor genes

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9
Q

What are oncogenes?

A

Activating mutations allow cells to grow in absence of signals

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10
Q

What are tumor suppressor genes?

A

Inactivating mutations overriding checkpoints that prevent growth or cause cell death

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11
Q

What happens to the dividing cells of a tumor as it increases in size?

A

The number of dividing cells decrease

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12
Q

Why do you need multiple rounds of chemo?

A

Inactive cells can go into remission but can reactivate down the raod

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13
Q

Where do most cancer metastasize to? Why?

A

Liver and lungs - increased capillary beds so pressure/speed is lower then the rest of the body. Gives tumor cells time to set up shop

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14
Q

How are ways that cancer cell mutations act on the cancer cell itself?

A

Genome instabilty/mutation, resisting cell death, deregulating cellular energetics, sustained proliferative signaling, and enabling replicative immortality

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15
Q

What are ways that cancer cell mutations act with the environment?

A

Evading growth suppressors, avoiding immune destruction, tumor promoting inflammation, inducing angiogenesis, and activating invasion/metastasis

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16
Q

What are the three major goals of cancer treatment?

A

Cure, induce remission, and palliative treatment

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17
Q

Cure -

A

Elimination of ALL cancer cells from the body

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18
Q

Why is it hard to know if you CURED the cancer?

A

All it takes is one cell, and there is no test to determine if there was any cells left after treatment

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19
Q

Induce remission -

A

Absence of clinical signs of disease

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20
Q

Palliative treatment -

A

Pain reduction to improve quality of life

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21
Q

When is palliative treatment your best option?

A

Remission is unattainable or elderly patient where they couldn’t undergo treatment

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22
Q

What are the advantages of chemotherapy?

A

Good for treatment of diffuse disease, treatment of areas in difficult anatomic locations, and can improve the surgical outcome

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23
Q

What are the downsides to chemotherapy?

A

Solid tumors are resistant, cancer is constantly changing so might stop working, lots of adverse effects, and expensive

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24
Q

Drugs for: Anal sac adenocarcinomas

A

Doxorubicin, mitoxantrone, toceranib

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25
Q

Drugs for: TCC

A

Prioxicam + Mitoxantrone, carboplatin, gemcitabine; vinblastine, mitomycin C

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26
Q

Drugs for: Multiple myeloma

A

melphalan + prednisone

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27
Q

Drugs for: Osteosarcoma

A

Doxorubicin, carboplatin, cisplatin, and gemcitabine

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28
Q

Drugs for: Mast cell tumors

A

Toceranib and mastinib

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29
Q

Drugs for: SSC

A

Paclitaxel and mitomycin C

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30
Q

Drugs for: Lymphoma, remission

A

CHOP protocol (Cyclophosphamide, Hydroxydaunorubicin, Oncovin, and Prednisone)

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31
Q

Drugs for: Lymphoma, rescue

A

ALL DA DRUGS

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32
Q

Why is it important do do chemotherapy with osteosarcoma even if you have amputated the leg?

A

95 to 100% of dogs where symptoms of osteosarcoma are present have mets to the lungs already

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33
Q

What are the six groups of chemotherapy drugs?

A

Alkylating agents, anthracyclines, pyrimidine analogs, drugs affecting tubulin, tyrosine kinase inhibitors, and three other drugs

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34
Q

What are the four types of alkylating agents?

A

Nitrogen mustards, platinum agents, methylating agents, and 2 other drugs

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35
Q

Alkylating agents - Nitrogen mustards:

A

Cyclophosphamide, mechlorethamine, and melphalan

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36
Q

Alkylating agents - Platinum agents:

A

Cisplatin and carboplatin

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37
Q

Alkylating agents - Methylating agents

A

Dacarbazine, procarbazine, and temozolomide

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38
Q

Alkylating agents - Others:

A

Mitomycin C and lomustine

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39
Q

Anthracyclines:

A

Doxorubicin, mitoxantrones, and dactinomycin

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40
Q

Pyrimidine analogs:

A

Cytarabine and gemcitabine

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41
Q

Drugs affecting tubulin:

A

Vincristine, vinblastine, and paclitaxel

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42
Q

Tyrosine kinase inhibitors:

A

Toceranib and mastinib

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43
Q

What are the three chemotherapy agents that dont really belong to a specific group?

A

Asparaginase, prednisone, and piroxicam

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44
Q

What is the chemical structure of the alkylating agents that allows them to be reactive?

A

The chlorides

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45
Q

How do the alkylating agents work?

A

Causes crosslinking in the DNA strand. DNApol can no longer read the DNA. Leads to replication and transcription inhibition, cell-cycle arrest, DNA repair, and cell death

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46
Q

What is the major target within the DNA for the alkylating agents?

A

G N7 position

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47
Q

What are the drugs that cause single cross links?

A

Dacarbizine, procarbazine, and temozolamide

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48
Q

What are the drugs that cause double cross links?

A

Cyclophosphamide, mechlorethamine, melphalan, cisplatin, carboplatin, lomustine, and mitomycin C

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49
Q

What direct effects does the alkylating agents have on the DNA strand?

A

Deletion of modified G’s from DNA during replication. Mispairing of modified G’s to T rather than C. Leads to so many mutations it causes cellular apoptosis.

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50
Q

What allows the alkylating agents to work so well?

A

Can effect the cell at ALL stages because will effect protein synthesis as well.

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51
Q

Which of the akylating agents are given PO?

A

Lomustine, melphalan, procarbazine, and cyclophosphamide

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52
Q

Which of the alkylating agents gets absorbed by the liver, bone, and GI tissue the best?

A

Platinum agents

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53
Q

Which of the alkylating agents crosses the BBB?

A

Procarbazine

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54
Q

How are the platinum alkylating agents metabolize in the body?

A

They are not actively metabolized, eliminated as the parent drug

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55
Q

Which of the alkylating agents have active metabolites?

A

Lomustine and cyclophosphamide

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56
Q

Which of the alkylating agents is metabolized in the plasma? How?

A

Melphalan - via hydrolysis

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57
Q

How are the platinum compounds excreted?

A

Active renal secretion, both parent drug and free platinum are excreted

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58
Q

What is the major downside of using platinum compounds?

A

They are secreted in the urine as an active compound for 5 days post treatment making disposal of waste hard.

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59
Q

Dose limiting toxicity -

A

Dose that causing the most severe toxic effects taht doesn’t kill a patient

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60
Q

What is the most dose limiting effect of Lomustine, mechlorethamine, melphalan, and procarbazine? Why?

A

Myelosuppression, increases the risk the patient might get an infection which they will not be able to fight off

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61
Q

What are the adverse effects of Lomustine, mechlorethamine, melphalan, and procarbazine? When do you start to see these effects?

A

Myelosuppression and thromnbocytopenia. Delayed effect because it is affecting the immature cells so won’t see problems till these cells mature.

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62
Q

Which of the alkylating agents myelosuppression is additive?

A

Lomustine

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63
Q

What are the adverse effects of cyclophosphamide?

A

Necrotizing hemorrhagic cystitis

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64
Q

What are the adverse effects of cisplatin?

A

Leukopenia and acute nephrotoxicity in dogs

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65
Q

What happens in cats that are given cisplatin?

A

Lethal pulmonary edema

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66
Q

What are the adverse effects of carboplatin?

A

Only causes leukopenia

67
Q

What causes there to be a vesicant effect of the alkylating drugs?

A

Active form of these drugs cause free radicals. If these free radicals are able to get outside the circulation they cause severe tissue damage.

68
Q

What are three ways that a tumor cell becomes resistant to a drug?

A

Increase production of molecules that inactivate drug, increase DNA repair enzymes, or reduce the intracellular drug concentrations

69
Q

How is melphalan taken up by the cell?

A

Leucine transport system

70
Q

How is mechlorethamine taken up by the cell?

A

Chloine transport system

71
Q

Besides reducing expression of enzymes that transport the drug into the cell what is another way a tumor cell can have less drug in the cell?

A

Increase the export enzymes (P-gp)

72
Q

What inactivates cyclophosphamide?

A

Aldehyde dehydrogenase

73
Q

What competes with DNA for the alkylating drugs?

A

Glutathione

74
Q

What is the most common antracyclines?

A

Doxorubicin

75
Q

How does doxorubicin cause oxygen radicals?

A

DNA damage leading to apoptosis. Lipid peroxidation of cell membranes

76
Q

What does lipid peroxidation do to the cell?

A

Makes it leaky and therefor causes cell death

77
Q

What drugs inhibit topiosomerase II?

A

Doxorubicin and mitoxantrone

78
Q

What happens when Topoisopermase II is inhibited?

A

Blocks DNA replication and reduces RNA/protein synthesis

79
Q

What does Dactionmycin inhibit?

A

DNA-Dependent RNA synthesis

80
Q

How are anthracyclines administered?

A

All given IV, IP can be done for more of a local deposition.

81
Q

Where do anthracyclines not distribute to? Why?

A

CNS, due to P-gp

82
Q

Where are anthracyclines metabolized?

A

Hepatic

83
Q

What is the major metabolite of antracyclines?

A

Doxorubicinol

84
Q

How is doxorubicin eliminated?

A

Excreted in feces for the most part, 10% is excreted in the urine

85
Q

How long is doxorubicin detected in the waste of an animal?

A

14 days

86
Q

How is mitoxanthrone eliminated?

A

100% unchanged within the urine

87
Q

How is Dactinomycin eliminated?

A

Most of it is eliminated unchanged in the urine and feces

88
Q

What are the adverse effects of doxorubicin in the early stages of administration (

A

Nausea, vomiting, histamine release, ventricular arrythmia, and acute GI toxicity

89
Q

What happens if you are getting ventricular arryhtmias with doxorubicin adminstration?

A

Slow the adminstration of the medication

90
Q

What are the intermediate (1d to 2 weeks) adverse effects of doxorubicin use?

A

Alopecia, thrombocytopenia, neutropenia, tissue inflammation/necrosis

91
Q

What is the dose limiting adverse effect when it comes to doxorubicin?

A

Thrombocytopenia and neutropenia

92
Q

When do you see tissue inflammation and necrosis with doxorubicin?

A

When it gets out of the circulatory system during administration due to the creation of free radicals

93
Q

What are the chronic side effects of doxorubicin effects in dogs?

A

Dilated cardiomyopathy

94
Q

How does DCM occur in dogs on doxorubicin?

A

Oxygen radicals damage cardiomyocyte sarcoplasmic reticulum, damage accumulates and DCM occurs

95
Q

Is DCM a dose limiting effect on doxorubicin treatment?

A

No, it is a treatment limiting effect though. If it occurs then treatment must be stopped and another drug needs to be used.

96
Q

What dogs are most susceptible to DCM from doxorubicin?

A

ABCB1-/-

97
Q

What does chronic doxorubicin use in cats cause?

A

Chronic renal failure

98
Q

How does chronic renal failure occur in cats using doxorubicin?

A

Oxygen radicals damage podocytes of renal glomeruli, damage accumulates. Need to monitor closely because known at what dose this occurs.

99
Q

What are the adverse effects of Dactinomycin?

A

Myelosuppression, diarrhea, ulcerative stomatitis, urate stone formation, and vesicant

100
Q

What are the adverse effects of Mitoxantrone?

A

Vomiting, diarrhea, anorexia, and myelosuppression

101
Q

How does resistance form against anthracyclines?

A

Increased p-gp expression. Increased glutathione expression for doxo and dactino.

102
Q

What is the base used in pyrimidine analogs?

A

Cytosine

103
Q

At what phase do the pyrimidine analogs work?

A

S phase only! Due to the affecting the creating of a DNA strand

104
Q

How do the pyrimidine analogs work?

A

DNA polymerase can’t read modified sugar nucleosides. Bases are “repaired” leading to an increasing amount of mutations. Ends with the death of the daughter cell

105
Q

Which of the pyrimidine analogs are most effective?

A

Cytarabine

106
Q

How are pyrimidine analogs administered?

A

IV or SC (Gemcitabine is IV only)

107
Q

What determines how much pyrimidine analog gets into the CNS?

A

CRI > Bolus, making CNS adverse effects more prominent with CRI’s

108
Q

How are pyrimidine analogs metabolized?

A

Converted to Ara-U in liver and kidneys by cytosine deaminase

109
Q

How are pyrimidine analogs eliminated?

A

urinary

110
Q

What are the adverse effects of the pyrimidine analogs?

A

Myelosuppression, leukopenia is most common. But anemia and thrombocytopenia can occur as well

111
Q

How does resistance occur against pyrimidine analogs?

A

Increased expression of p-gp. increased expression of cytosine deaminase

112
Q

What are the two types of chemotherapy agents that affect tubulin dynamics?

A

Vinca alkaloids and taxanes

113
Q

Taxanes -

A

Paclitaxel

114
Q

Vinca alkaloids -

A

Vincristine and vinblastine

115
Q

How do the drugs that affect tubulin dynamics work?

A

Act to stabilize microtubules. Prevent proper breakdown of mitotic spindle during cytokinesis. Induce apoptosis and immune clearance.

116
Q

At what phase of cell replication do tubulin dynamic drugs work?

A

M-Phase

117
Q

Which of the tubulin dynamic drugs may work synergistically? Why?

A

Vincristine and paclitaxel sites differ so they can attack two different locations.

118
Q

How are the tubulin dynamic drugs administered?

A

IV

119
Q

How are the tubulin dynamic drugs distributed throughout the body?

A

Plasma protein binding occurs. But excluded from the CNS via p-gp

120
Q

How are tubulin dynamic drugs metabolized?

A

Liver

121
Q

How are tubulin dynamic drugs metabolized?

A

Fecal, in biphasic manner

122
Q

What does the biphasic response of tubulin dynamic drugs suggest?

A

Slow elimination following tissue accumulation

123
Q

What are the major adverse effects seen when using tubulin dynamic drugs?

A

Neurotoxicity and histamine release

124
Q

What is the dose limiting toxicity for the tubulin drugs?

A

Neurotoxicity

125
Q

Which of the tubulin drugs is the most neurotoxic?

A

Vincristine

126
Q

What neuro symptoms are seen with toxicity caused by tubulin drugs

A

Difficulty with movement, paresis, and voice change. Improvement does occur when drugs are discontinued

127
Q

Which of the tubulin drugs causes a histamine release?

A

Paclitaxel

128
Q

What must be given with Paclitaxel?

A

Anti-histamines

129
Q

What causes the histamine release when paclitaxel is adminstered?

A

Due to the vechile that the drug is dissolved in

130
Q

What is the catch-22 with Paclitaxel adminstration?

A

Rapid infusion - histamine release. But slow infusion causes myelosuppression.

131
Q

Which of the tubulin drugs is more myelosuppressive?

A

Vinblastine

132
Q

How do cancer cells become resistant to tubulin drugs?

A

p-gp mutations and other

133
Q

What does the activation of tyrosine kinase receptors cause?

A

Many cellular responses. Most common being: proliferation and protein synthesis.

134
Q

What phase of the cycle is affected by drugs that target receptor tyrosine kinases?

A

G1 phase

135
Q

What is c-kit?

A

Oncogene, responsible for a receptor tyrosine kinases (CD117). This is a stem cell growth factor receptor. Driving leukopoesis.

136
Q

Where are c-kit mutations most commonly seen?

A

Mast cell tumors

137
Q

What happens when the c-kit oncogene is turned on?

A

Causes continous signaling from the receptor, even without a ligand. Leading to unregulated cell proliferation.

138
Q

How do the receptor tyrosine kinases inhibitors work?

A

Act as a competitive antagonist of ATP binding to the kinase domain of c-kit

139
Q

What are the targets of masitinib?

A

c-kit, PDGF-R, and Lyn

140
Q

What are the targets of tocerinib?

A

c-kit, and 50 more tyrosine kinases

141
Q

What is the route of elimination for mastinib?

A

Fecal

142
Q

How are the tyrosine kinases metabolized?

A

hepatic

143
Q

What are the adverse effects of toceranib?

A

Diarrhea, anorexia, weight loss, melena, lameness, anemia, neutropenia, and thromboembolism

144
Q

What are the adverse effects of masitinib?

A

Vomiting, diarrhea, hepatotoxicity, neutropenia, renal toxicity, anemia

145
Q

What is prednisone?

A

Glucocorticoid with broad anti-inflammatory effects

146
Q

What is the DOC for TCC?

A

Piroxicam

147
Q

How does piroxicam work?

A

Nonspecific cyclooxygenase inhibitor

148
Q

How is piroxicam metabolized?

A

Liver

149
Q

How is piroxicam eliminated?

A

Urine

150
Q

What are the adverse effects of piroxicam?

A

GI ulceration, renal papillary necrosis

151
Q

How does asparaginase work?

A

Stops Asp –> ASN in lymphoid tumors

152
Q

At what point of the cell cycle does asparaginase work?

A

G1 phase

153
Q

How is asparaginase adminstered?

A

IV

154
Q

How is asparaginase distributed in the body

A

Confined to the plasma

155
Q

How long do asparagine levels remain low when a patient is given asparaginase?

A

23 days post administration

156
Q

How is asparaginase used metabolized?

A

Hydrolyzed into amino acids and then used for new protein synthesis

157
Q

What are the two major toxic side effects of asparaginase use?

A

Hypersensitivity and protein synthesis abnormalities

158
Q

What are the signs of protein synthesis abnormalities caused by asparaginase?

A

Hepatotoxicity, coagulation defects, hemorrhagic pancreatitis, and hyperglycemia

159
Q

What part of the cell cycle does prednisone and piroxicam work on?

A

Cell cycle independent

160
Q

Drugs that - Work on cellular energetics

A

Asparaginase

161
Q

Drugs that - Effect the proliferative signaling

A

Receptor tyrosine kinase inhibitors

162
Q

Drugs that - Affect tumors cells resistance to death

A

Alkylating agents, anthracyclines, pyrimidine analogs, and microtubule stabilizers

163
Q

Drugs that - Affect the tumor-promoting inflammation

A

Prednisone and piroxicam

Pharmacology II (20 decks)

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