LEC 27,28 - Anti-Neoplastics Flashcards Preview

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

Flashcards in LEC 27,28 - Anti-Neoplastics Deck (163):
1

What replicative phase do most mature animals enter?

G0 - will then reactivate with injury

2

What cells in the body have constant replication?

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

3

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

Presence of growth signals and check points

4

What are the six replication check points?

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

5

What happens in the spindle checkpoint.

Make sure that things are seperating correctly

6

What happens in the antephase checkpoint?

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

7

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

Proofread the daughter cell for DNA mistake

8

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

Oncogenes or tumor suppressor genes

9

What are oncogenes?

Activating mutations allow cells to grow in absence of signals

10

What are tumor suppressor genes?

Inactivating mutations overriding checkpoints that prevent growth or cause cell death

11

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

The number of dividing cells decrease

12

Why do you need multiple rounds of chemo?

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

13

Where do most cancer metastasize to? Why?

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

14

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

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

15

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

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

16

What are the three major goals of cancer treatment?

Cure, induce remission, and palliative treatment

17

Cure -

Elimination of ALL cancer cells from the body

18

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

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

19

Induce remission -

Absence of clinical signs of disease

20

Palliative treatment -

Pain reduction to improve quality of life

21

When is palliative treatment your best option?

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

22

What are the advantages of chemotherapy?

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

23

What are the downsides to chemotherapy?

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

24

Drugs for: Anal sac adenocarcinomas

Doxorubicin, mitoxantrone, toceranib

25

Drugs for: TCC

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

26

Drugs for: Multiple myeloma

melphalan + prednisone

27

Drugs for: Osteosarcoma

Doxorubicin, carboplatin, cisplatin, and gemcitabine

28

Drugs for: Mast cell tumors

Toceranib and mastinib

29

Drugs for: SSC

Paclitaxel and mitomycin C

30

Drugs for: Lymphoma, remission

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

31

Drugs for: Lymphoma, rescue

ALL DA DRUGS

32

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

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

33

What are the six groups of chemotherapy drugs?

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

34

What are the four types of alkylating agents?

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

35

Alkylating agents - Nitrogen mustards:

Cyclophosphamide, mechlorethamine, and melphalan

36

Alkylating agents - Platinum agents:

Cisplatin and carboplatin

37

Alkylating agents - Methylating agents

Dacarbazine, procarbazine, and temozolomide

38

Alkylating agents - Others:

Mitomycin C and lomustine

39

Anthracyclines:

Doxorubicin, mitoxantrones, and dactinomycin

40

Pyrimidine analogs:

Cytarabine and gemcitabine

41

Drugs affecting tubulin:

Vincristine, vinblastine, and paclitaxel

42

Tyrosine kinase inhibitors:

Toceranib and mastinib

43

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

Asparaginase, prednisone, and piroxicam

44

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

The chlorides

45

How do the alkylating agents work?

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

46

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

G N7 position

47

What are the drugs that cause single cross links?

Dacarbizine, procarbazine, and temozolamide

48

What are the drugs that cause double cross links?

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

49

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

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.

50

What allows the alkylating agents to work so well?

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

51

Which of the akylating agents are given PO?

Lomustine, melphalan, procarbazine, and cyclophosphamide

52

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

Platinum agents

53

Which of the alkylating agents crosses the BBB?

Procarbazine

54

How are the platinum alkylating agents metabolize in the body?

They are not actively metabolized, eliminated as the parent drug

55

Which of the alkylating agents have active metabolites?

Lomustine and cyclophosphamide

56

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

Melphalan - via hydrolysis

57

How are the platinum compounds excreted?

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

58

What is the major downside of using platinum compounds?

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

59

Dose limiting toxicity -

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

60

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

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

61

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

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

62

Which of the alkylating agents myelosuppression is additive?

Lomustine

63

What are the adverse effects of cyclophosphamide?

Necrotizing hemorrhagic cystitis

64

What are the adverse effects of cisplatin?

Leukopenia and acute nephrotoxicity in dogs

65

What happens in cats that are given cisplatin?

Lethal pulmonary edema

66

What are the adverse effects of carboplatin?

Only causes leukopenia

67

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

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

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

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

69

How is melphalan taken up by the cell?

Leucine transport system

70

How is mechlorethamine taken up by the cell?

Chloine transport system

71

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?

Increase the export enzymes (P-gp)

72

What inactivates cyclophosphamide?

Aldehyde dehydrogenase

73

What competes with DNA for the alkylating drugs?

Glutathione

74

What is the most common antracyclines?

Doxorubicin

75

How does doxorubicin cause oxygen radicals?

DNA damage leading to apoptosis. Lipid peroxidation of cell membranes

76

What does lipid peroxidation do to the cell?

Makes it leaky and therefor causes cell death

77

What drugs inhibit topiosomerase II?

Doxorubicin and mitoxantrone

78

What happens when Topoisopermase II is inhibited?

Blocks DNA replication and reduces RNA/protein synthesis

79

What does Dactionmycin inhibit?

DNA-Dependent RNA synthesis

80

How are anthracyclines administered?

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

81

Where do anthracyclines not distribute to? Why?

CNS, due to P-gp

82

Where are anthracyclines metabolized?

Hepatic

83

What is the major metabolite of antracyclines?

Doxorubicinol

84

How is doxorubicin eliminated?

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

85

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

14 days

86

How is mitoxanthrone eliminated?

100% unchanged within the urine

87

How is Dactinomycin eliminated?

Most of it is eliminated unchanged in the urine and feces

88

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

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

89

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

Slow the adminstration of the medication

90

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

Alopecia, thrombocytopenia, neutropenia, tissue inflammation/necrosis

91

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

Thrombocytopenia and neutropenia

92

When do you see tissue inflammation and necrosis with doxorubicin?

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

93

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

Dilated cardiomyopathy

94

How does DCM occur in dogs on doxorubicin?

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

95

Is DCM a dose limiting effect on doxorubicin treatment?

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

96

What dogs are most susceptible to DCM from doxorubicin?

ABCB1-/-

97

What does chronic doxorubicin use in cats cause?

Chronic renal failure

98

How does chronic renal failure occur in cats using doxorubicin?

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

99

What are the adverse effects of Dactinomycin?

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

100

What are the adverse effects of Mitoxantrone?

Vomiting, diarrhea, anorexia, and myelosuppression

101

How does resistance form against anthracyclines?

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

102

What is the base used in pyrimidine analogs?

Cytosine

103

At what phase do the pyrimidine analogs work?

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

104

How do the pyrimidine analogs work?

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

Which of the pyrimidine analogs are most effective?

Cytarabine

106

How are pyrimidine analogs administered?

IV or SC (Gemcitabine is IV only)

107

What determines how much pyrimidine analog gets into the CNS?

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

108

How are pyrimidine analogs metabolized?

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

109

How are pyrimidine analogs eliminated?

urinary

110

What are the adverse effects of the pyrimidine analogs?

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

111

How does resistance occur against pyrimidine analogs?

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

112

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

Vinca alkaloids and taxanes

113

Taxanes -

Paclitaxel

114

Vinca alkaloids -

Vincristine and vinblastine

115

How do the drugs that affect tubulin dynamics work?

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

116

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

M-Phase

117

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

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

118

How are the tubulin dynamic drugs administered?

IV

119

How are the tubulin dynamic drugs distributed throughout the body?

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

120

How are tubulin dynamic drugs metabolized?

Liver

121

How are tubulin dynamic drugs metabolized?

Fecal, in biphasic manner

122

What does the biphasic response of tubulin dynamic drugs suggest?

Slow elimination following tissue accumulation

123

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

Neurotoxicity and histamine release

124

What is the dose limiting toxicity for the tubulin drugs?

Neurotoxicity

125

Which of the tubulin drugs is the most neurotoxic?

Vincristine

126

What neuro symptoms are seen with toxicity caused by tubulin drugs

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

127

Which of the tubulin drugs causes a histamine release?

Paclitaxel

128

What must be given with Paclitaxel?

Anti-histamines

129

What causes the histamine release when paclitaxel is adminstered?

Due to the vechile that the drug is dissolved in

130

What is the catch-22 with Paclitaxel adminstration?

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

131

Which of the tubulin drugs is more myelosuppressive?

Vinblastine

132

How do cancer cells become resistant to tubulin drugs?

p-gp mutations and other

133

What does the activation of tyrosine kinase receptors cause?

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

134

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

G1 phase

135

What is c-kit?

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

136

Where are c-kit mutations most commonly seen?

Mast cell tumors

137

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

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

138

How do the receptor tyrosine kinases inhibitors work?

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

139

What are the targets of masitinib?

c-kit, PDGF-R, and Lyn

140

What are the targets of tocerinib?

c-kit, and 50 more tyrosine kinases

141

What is the route of elimination for mastinib?

Fecal

142

How are the tyrosine kinases metabolized?

hepatic

143

What are the adverse effects of toceranib?

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

144

What are the adverse effects of masitinib?

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

145

What is prednisone?

Glucocorticoid with broad anti-inflammatory effects

146

What is the DOC for TCC?

Piroxicam

147

How does piroxicam work?

Nonspecific cyclooxygenase inhibitor

148

How is piroxicam metabolized?

Liver

149

How is piroxicam eliminated?

Urine

150

What are the adverse effects of piroxicam?

GI ulceration, renal papillary necrosis

151

How does asparaginase work?

Stops Asp --> ASN in lymphoid tumors

152

At what point of the cell cycle does asparaginase work?

G1 phase

153

How is asparaginase adminstered?

IV

154

How is asparaginase distributed in the body

Confined to the plasma

155

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

23 days post administration

156

How is asparaginase used metabolized?

Hydrolyzed into amino acids and then used for new protein synthesis

157

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

Hypersensitivity and protein synthesis abnormalities

158

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

Hepatotoxicity, coagulation defects, hemorrhagic pancreatitis, and hyperglycemia

159

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

Cell cycle independent

160

Drugs that - Work on cellular energetics

Asparaginase

161

Drugs that - Effect the proliferative signaling

Receptor tyrosine kinase inhibitors

162

Drugs that - Affect tumors cells resistance to death

Alkylating agents, anthracyclines, pyrimidine analogs, and microtubule stabilizers

163

Drugs that - Affect the tumor-promoting inflammation

Prednisone and piroxicam