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Flashcards in Anti-Neoplastic Agents Deck (105):
1

Cell cycle:******

Occurs throughout development of an animal.
Slows in most tissues of mature and healthy animals (cells enter G0, reactivate with injury)

2

Exceptions of normal slowing of the cell cycle?

Skin, hair follicles, GI epithelium, bone marrow**** and male gametes.

3

Normal progression through the cell cycle is regulated by..

Presence of growth signals and check points.
IGF1 can stimulate cell growth.
-3 check points, check for DNA damage, making sure both copies are intact and surveying for environmental damage.

4

Cancer cells must have mutations in.. (2)

Oncogenes and Tumor suppressor genes.
*Bypass the normal DNA damage checkpoints.

5

What are oncogenes?

Activating mutations, promotes cell growth in the absence of growth signals.

6

What are tumor suppressor genes?

Inactivating mutations
Over-ride checkpoints that prevent growth or cause cell death.
*Shuts down cell communication.

7

What are the hallmarks of cancer?

A tumor is more than just a mass of cells progressing, uncontrolled through the cell cycle...
Fraction of dividing cells in a tumor, DECREASES as the tumor size increases..
-Inactive cells "senesce" but can reactivate *this is the limiting factor in treating cancer.
-not all chemotherapeutic agents work on all cells
*Tumor can change the physiology and signal to different organs/sites.

8

What is the biggest limiting factor in treating cancer?

Inactive cells "senesce" but can reactivate

9

Cancer mass composed of..

Endothelial cells, blood supply, inflammatory responses,..
Not all cells are dividing.

10

Hallmarks of cancer; contribution of mutations to cancer..
Acting on cancer cells:

Genome instability and mutation.
Resisting cell death
Deregulating cellular energetics
Sustained proliferative signaling
Enabling replicative immortality.

11

Hallmarks of cancer; contribution of mutations to cancer..
Acting on the MICROENVIRONMENT:

Evading growth suppressors
Avoiding immune destruction
Tumor promoting inflammation
Inducing angiogenesis
Activating invasion and metastasis

12

What are the goals of cancer treatment?

Cure= elimination of all cancer cells from the body (rare)
Induce remission = absence of clinical signs of disease.
Palliative treatment = pain reduction to improve quality of life
-If remission is unattainable, if an elderly animal can have an improved quality of life and clients elect not to pursue remission.
While a cure is an ideal goal, remission and palliation are both worthy goals.

13

What are advantages of chemotherapy?

Treatment of diffuse disease (lymphoma and leukemia)
Treatment of areas in difficult anatomic locations (brain tumors)
Improved surgical outcome

14

What are the disadvantages of chemotherapy?

Solid tumors (>1mg of tissue) are resistant
Selection for resistant cells
Adverse effects
Expensive (local lesions in horses are amendable, but not large or systemic disease, livestock aren't safe for food use after chemotherapy)

15

Can livestock use chemotherapy agents?

NO- aren't safe for use.

16

*********What is the CHOP protocol?

Used to induce remission/reinducton.
Used for lymphoma *most common cancer*
Cyclophosphamide
Hydroxydaunorubin (doxorubicin)
Oncovin (vincristine)
Prednisone

*Reduction is the second time

17

What two drugs at protein tyrosine kinase inhibitors developed specifically for dogs?

Toceranic (mast cells)
Mastinib (mast cells)

18

Alkylating agents:
Nitrogen Mustards:
drugs include..
(Anti-neoplastic)

Cyclophosphamide
Mechlorethamine
Melphalan

19

Alkylating agents:
Platinum agents, drugs include..
(Anti-neoplastic)

Cisplatin and caroplatin

20

Alkylating agents
Methylating agents
Drugs include..
(Anti-neoplastic)

Dacarbazine
Procarbazine
Temozolomide

21

Alkylating agents:
Misc (2) two drugs:
(Anti-neoplastic)

Mitomycin C and lomustine

22

Anthracyclines
(Anti-neoplastic)
Drugs include..

Doxorubicin
Mitoxantrone
Dactinomycin

23

Pyrimidine Analogs
(Anti-neoplastic)
Drugs include..

Cytarabine
Gemcitabine

24

Drugs affecting tubulin (break down of spindles during mitosis)
Drugs include..
(Anti-neoplastic)

Vincristine
Vinblastine
Paclitaxel

25

(Anti-neoplastic)
Tyrosine Kinase Inhibitors
Drugs include (2)

Toceranib
Mastinib

26

(Anti-neoplastic)
Misc. Drugs (3)

Asparaginase
Predinsone
Piroxicam******

27

All alkylating (Anti-neoplastic) drugs all make use of what element in their structure?

Chlorine

28

******Anti-neoplastic)
Alkylating agents
MOA:

Chlorine atoms can crosslink and modify the bases of guanine molecules. Causes cell death.
These drugs can saturate the DNA.
Covalent bonding/cross-linking to DNA bases.
Guanine bases react preferentially; deletion of modified guanines****** from DNA during replication, mispairing of modified quanines with thymine vs cytosine during replication.
Ultimately the agents cause enough mutation induce cell apoptosis.******
*These drugs affect ALL stages of the cell cycle.******

29

(Anti-neoplastic)
Alkylating agents
Covalent bonding/cross-linking to DNA bases
-single cross-linking drugs?

decarbazine, procarbazine, and temozolamide

30

(Anti-neoplastic)
Alkylating agents
Covalent bonding/cross-linking to DNA bases
-double cross-linking drugs?

cyclophosphamide, mechlorethamine, melaphalan, cisplatin, carboplatin, lomustine and mitomycin C
*can form inter-base cross-links.

31

(Anti-neoplastic)
Alkylating agents effect what stages of the cell cycle?

ALL STAGES

32

(Anti-neoplastic)
Alkylating agents
Absorption
What agents are pro-drugs?

Most drugs are administered IV
Lomustine, melpalan, procabazine and cyclphophamide are PO (pro-drugs)

33

(Anti-neoplastic)
Alkylating agents
Distribution:

Rapidly distributed through the body
Platinum agents are most strongly absorbed by liver, bone and GI tissue.
Procarbazine and active metabolites of lomustine cross the BBB.
Plasma protein binding is variable (~90% of cisplatin binds to albumin, carboplatin does not)

34

(Anti-neoplastic)
Alkylating agents
Metabolism

Platinum compounds are not actively metabolized.
Decarbonizne is a pro-drug (the active drug is temozolamide)
Lomustine and cyclophosphamide are pro-rugs metabolized to their active forms.
Melphalan s metabolized in the plasma by hydrolysis.

35

Elimination
(Anti-neoplastic)
Alkylating agents

Platinum compounds undergo active RENAL secretion (will release the drug in the environment for 3 days)
Cyclphosphamide: 1 hour
Lomustine: 15 minutes

36

******(Anti-neoplastic)
Alkylating agents
Toxicity/Adverse effect:
Vesciation: ******

-Blistering and erosion, not vesiculation, iatrogenic.
Severe tissue damage resulting form the drug getting out of circulation (extravasated)
-Prodrugs administerd PO aren't vesicants until they are converted to the active form (lower risk)
-Active drugs (administered IV) are ALWAYS vesicants, higher risk, requiring CAREFUL catheter placement.

37

******(Anti-neoplastic)
Alkylating agents
Toxicity/Adverse effect:
Vesciation:
MOA

The active forms of all alkylating agents develop free radicals, free radicals cause severe tissue damage outside of the circulation.

38

******(Anti-neoplastic)
Alkylating agents
Toxicity/Adverse effect:
DOSE-LIMITING toxicity:

The most severe toxic effect of a drug that doesn't lead to acute death.
Corresponds to the highest dose of a drug that can be given to the patient without death (highest tolerable dose)
This is the dosing goal for all anti-neoplastic agents.
-kills most cancer cells
-reduces risk of developing resistant cancer cells.

39

******Lomustine, mechlorethamine, melphalan and procarbazine
Specific dose limiting toxicities:

Myelosuppression and thrombocytopenia
CUMULATIVE myelosuppression for lomustine
Delayed effect (days to weeks)

40

******Specific dose limiting toxicities:
Cyclophosphamide:

Necrotizing hemorrhagic cystitis

41

******Specific dose limiting toxicities:
Cisplatin

Leukopenia
LETHAL PULMONARY EDEMA in cats******
Acute nephrotoxicity in dogs ******

LETHAL IN CATS = CISPLATIN

42

Specific dose limiting toxicities:
Carboplatin

Only causes leukopenia

43

Resistance mechanisms
(Anti-neoplastic)
Alkylating agents

Increased production of molecules that inactivate drugs..
-Aldehyde dehydrogenase inactivates cyclophosphamide
-Glutathione competes with DNA for the drugs (reduced glutathione is a free radical scavenger)
Increased expression of DNA repair enzymes
Reduction of intracellular drug concentrations by..
-Reducing expression of enzymes that transport the drug into the cell (melphalan is taken in by leucine transport system, mechlorethamine is taken in by the chlorine transport system) OR increasing expression of enzymes that export the drug (p-gp)
*Mechanisms occur in the cancer cells
Resistance to one alkylating agent does not imply resistance to all alkylating agents, but does not PRECLUE resistance to other agents.

44

Canine lymphoma left untreated, mean survival time is 4 to 6 weeks.
Treated with doxorubicin alone..

5% cured.
80-90% have 8 to 10 months 1st remission.

45

******Anthracyclines
(doxorubincin, mitoxanthrone, dactinomycin)
P.Dynamics

Intercalation into DNA
-Docorubicin and mitoxantrone inhibit topoisomerase II
--Blocks DNA replication and reduces RNA/protein synthesis.
-Dactinomycin inhibits DNA-dependent RNA synthesis
*These agents act during ALL phases of the cell cycle.

46

Anthracyclines
(doxorubincin, mitoxanthrone, dactinomycin)
Act during what phase of the cell cycle?

ALL phases of the cell cycle.

47

Anthracyclines
(doxorubincin, mitoxanthrone, dactinomycin)
Absorption:

All administered IV
Other routes (including IP) cause local deposition.
*NEED GOOD CATHETER STICKS*

48

Anthracyclines
(doxorubincin, mitoxanthrone, dactinomycin)
Distribution

Rapid distribution to all tissues.
Excluded from the CNS by P-gp (problem in collies)
75% bound to plasma albumin.

49

Anthracyclines
(doxorubincin, mitoxanthrone, dactinomycin)
Do not give in what species

Collies!
Excluded from the CNS by P-gp

50

Anthracyclines
(doxorubincin, mitoxanthrone, dactinomycin)
Metabolism:

Hepatic
Doxorubicinol, major metabolite, retains biological activity

51

Anthracyclines
(doxorubincin, mitoxanthrone, dactinomycin)
Elimination

Doxorubicin: 40-50% of drug is excreted in feces (10%) in the urine.
Terminal 1/2 = 20-48 hours (detectable in waste for 14 days)
Mitoxanthrone - 100% is eliminated unchanged in the urine (~1/2 5 days)
Dactinomycin - most is eliminated unchanged in the urine and feces.

52

******Doxorubicin
Early adverse effects:

<24 hours
-Nausea and vomiting
-Histamine release + anaphylaxis (treat with epinephrine + corticosteroids)
-Ventricular arrhythmia (slow administration- listen to heart when giving this drug)
-Acute GI toxcity

53

******Doxorubicin
Intermediate adverse effects (1d to 2 weeks)

Alopecia (hair regrows, changes color)
Thrombocytopenia and neutropenia (dose limiting)
Tissue inflammation/necrosis (vesication) **VERY SEVERE; occurs with extravasation during administration, caused by oxygen radicals, mitigate with dexrazoxane (iron chelating agent)*********

54

******Doxorubicin
Chronic changes:

Dilated cardiomyopathy in DOGS
-oxygen free-radicals damage cardiomyocyte SR. damage accumulation sets an upper limit on the total dose a patient can safely receive and is dose limiting.
ABCB1 -/- drugs are more susceptible.
******Chronic renal failure in CATS; oxygen free radicals damage podocytes of renal glomeruli, damage accumulates (no dose limit established)******

55

******Dactinomycin
Adverse effects:

Myelosuppression (all linages, dose limiting)****
Diarrhea, ulcerative stomatitis, urate stone formation in dogs with SLC2A9 mutations (Dalmatians) and vesicant*

56

Mitoxantrone
Adverse effects:

Engineered to have lower toxicity
-vomiting, diarrhea, anorexia, myelosuppresion**DL

57

Anthracyclines
(doxorubincin, mitoxanthrone, dactinomycin)
Resistance:

Increased P-gp expression
Increased glutathione expression which reduces free radical production increases resistance to doxorubicin.

58

******Pyrimidine analogs
(anti-neoplastic drugs)
Cytrarabine
Gemcitabine
Deoxycytidine
P.Dynamics:

Incorporated into the growing DNA strand during S-phase*****
DNA polymerase cant read modified sugars in the nucleosides, bases are "repaired" leading to extensive mutagenesis, death of the daughter cells.
Cytarabine is more effective in most vet studies.

59

Pyrimidine analogs
(anti-neoplastic drugs)
Cytrarabine
Gemcitabine
Deoxycytidine
Absorption:

Administered IV or SC (good BA)
gemcitabine is IV only!

60

Pyrimidine analogs
(anti-neoplastic drugs)
Cytrarabine
Gemcitabine
Deoxycytidine
Distribution

(plasma and some interstitial distribution)
amount passing into the CNS depends on the administration rate (CRI>bolus)

61

Pyrimidine analogs
(anti-neoplastic drugs)
Cytrarabine
Gemcitabine
Deoxycytidine
Metabolism

Converted to ARA-U in the liver and kidneys by cytosine deaminase

62

Pyrimidine analogs
(anti-neoplastic drugs)
Cytrarabine
Gemcitabine
Deoxycytidine
Elimination:

Urinary
1.5-3 hours (1/2)

63

Pyrimidine analogs
(anti-neoplastic drugs)
Cytrarabine
Gemcitabine
Deoxycytidine
Adverse effects:

Myelosuppression
-Leukopenia most common type, anemia and thrombocytopenia also occur.

64

Pyrimidine analogs
(anti-neoplastic drugs)
Cytrarabine
Gemcitabine
Deoxycytidine
Resistance:

Increased expression of P-gp
Increased expression of cytosine deaminase

65

Microtubule agents:
(anti-neoplastic drugs)
Vinca Alkaloids
-Vincristine (oncovin) *CHOP and Vinbalstine
Taxanes
-Paclitaxel
These drugs are similar to..

Bendimazoles

66

******Microtubule agents:
(anti-neoplastic drugs)
Vinca Alkaloids
-Vincristine (oncovin) *CHOP and Vinbalstine
Taxanes
-Paclitaxel
MOA:

Affects tubulin dynamics
*Acts to stabilize microtubules, prevents the proper breakdown of mitotic spindle during cytokinesis, induces apoptosis and immune clearance. acts during M-phase of the cell cycle.

67

******Microtubule agents:
(anti-neoplastic drugs)
Vinca Alkaloids
-Vincristine (oncovin) *CHOP and Vinbalstine
Taxanes
-Paclitaxel
Act during what phase of the cell cycle?

M PHASE

68

******Microtubule agents:
(anti-neoplastic drugs)
Vinca Alkaloids
-Vincristine (oncovin) *CHOP and Vinbalstine
Taxanes
-Paclitaxel
Sites of action

Vincristine and vinblastine sites are the same.
****Vincristine and paclitaxel sites differ, these drugs act synergistically!

69

Microtubule agents:
(anti-neoplastic drugs)
Vinca Alkaloids
-Vincristine (oncovin) *CHOP and Vinbalstine
Taxanes
-Paclitaxel
Absorption:

Administered IV

70

Microtubule agents:
(anti-neoplastic drugs)
Vinca Alkaloids
-Vincristine (oncovin) *CHOP and Vinbalstine
Taxanes
-Paclitaxel
Distribution:

Plasma protein binding (75% vinca, 98% paclitaxel)
Excluded from the CNS in P-gp (collies)
-increased toxic effects in ABCB1 (-/-) dogs
-VIncrisitine > vinblastine

71

Microtubule agents:
(anti-neoplastic drugs)
Vinca Alkaloids
-Vincristine (oncovin) *CHOP and Vinbalstine
Taxanes
-Paclitaxel
Metabolism

Hepatic

72

Microtubule agents:
(anti-neoplastic drugs)
Vinca Alkaloids
-Vincristine (oncovin) *CHOP and Vinbalstine
Taxanes
-Paclitaxel
Elimination:

GI
**Biphastic suggests slow elimination following tissue accumulation.
vincristine is the slowest (1/2) = 75 min.

73

******Microtubule agents:
(anti-neoplastic drugs)
Vinca Alkaloids
-Vincristine (oncovin) *CHOP and Vinbalstine
Taxanes
-Paclitaxel
Adverse effects:
DL effect?

Neurotoxicity****
-Dose limiting toxicity for all drugs in this class.
Mechanism is thought to be due to interaction with axonal microtubules.
Vincristine>vinblastine more neurotoxic, but vinblastine is more myelosuppressive******
**Signs** rapid onset, difficulty with locomotion, paresis, voice change, **improvement with discontinuation of the drug**

74

******Microtubule agents:
(anti-neoplastic drugs)
Vinca Alkaloids
-Vincristine (oncovin) *CHOP and Vinbalstine
Taxanes
-Paclitaxel
*Besides neurotoxicity, other adverse effects:

Histamine release, specifically paclitaxel, requires administration of antihistamines prior to treatment, produced by the VEHICLE the drug is dissolved in. Occurs with rapid infusion rates, but slower infusion rates can cause myelosuppresion.. :/ ******

75

Microtubule agents:
(anti-neoplastic drugs)
Vinca Alkaloids
-Vincristine (oncovin) *CHOP and Vinbalstine
Taxanes
-Paclitaxel
Myelosuppresion seen the most with.

Vinblastine >

76

Microtubule agents:
(anti-neoplastic drugs)
Vinca Alkaloids
-Vincristine (oncovin) *CHOP and Vinbalstine
Taxanes
-Paclitaxel
Resistance?

Cross resistance to vinblastine and vincristine does NOT occur**** unless there are P-gp mutations.

77

Tyrosine kinase inhibitors:
MOA:
******************

ATP binding site is blocked, cross phosphorylation.******
Receptor activation causes proliferation/mitogenic + protein synthesis. Drugs that target receptor tyrosine kinases block G1 phase****** of the cell cycle

78

Tyrosine kinase inhibitors block what phase of the cell cycle?

G1******

79

This receptor tyrosine kinase normally drives leikopoesis, especially in mast cells. Is an oncogene.

C-kit (CD117, steel factor receptor)

80

C-kit
Morphology

C-kit is an oncogene
-mutated in 25-50% of canine mast cell tumors
-mutant c-kit signals continuously even in the absence of the ligand (constitutive signaling)
-sufficient to cause unregulated cell proliferation of leukocytes, especially mast cells (driver mutation).

81

Mutation in this (driver mutation) can cause cancer alone

c-kit

82

Tyrosine kinase inhibitors:
Toceranib and Masitinib
P. dynamics:

Both are competitive antagonists of ATP binding to the kinase domain of c-kit.

83

Tyrosine kinase inhibitors:
Toceranib specificity:

c-kit
50 more tyrosine kinases

84

Tyrosine kinase inhibitors:
Masitinib specificity:

c-kit
PDGF-R (another receptor tyrosine kinase)
Lyn (intracellular tyrosine kinase)

85

Tyrosine kinase inhibitors:
Toceranib and Masitinib
Act on what phase of the cell cycle?

G1 phase

86

Tyrosine kinase inhibitors:
Toceranib and Masitinib
PK (dogs, oral administration):

BA 77-80% (mastinib increases with food)
High plasma protein binding
Hepatic metabolism
Fecal elimination
3-17 hours (t1/2)

87

Tyrosine kinase inhibitors:
Toceranib
Adverse effects:

Diarrhea, anemia + neutropenia**DLT
+ Melena, anorexia/weight loss, lameness, thromboembolism.

88

******Tyrosine kinase inhibitors:
Masitinib
Adverse effects:

Diarrhea, anemia + neutropenia***DL
Vomiting (>5 days), hepatotoxicity and renal toxicity.

89

******L-asparaginase is toxic to tumor cells (lymphoid cell tumors) because..

Effective against lymphoma.
Deprive necessary requirements for lymphoma cell growth.******
Toxic to the tumor cell because it cannot covert the aspartate into asparagine.******

Used as a rescue agent when they have failed responding retreatment to a CHOP protocol******

90

L-asparaginase acts at what phase during the cell cycle?

G1 phase******

91

L-asparaginase
Absorption:

Typically administered IV
50% BA when administered SC

92

L-asparaginase
Distribution:

Confined to the plasma, but rapidly becomes undetectable, levels remain low for 23 days post administration.

93

L-asparaginase
Metabolism and elimination:

Hydrolyzed to amino acids and used for new protein synthesis

94

******L-asparaginase
Hypersensitivity:

Pruritus, urticaria, dyspnea, vomiting and diarrhea.

95

L-asparaginase
Protein synthesis abnormalities

Hepatotoxicity
Defective coagulation factor production
-coagulation defects
-hemorrhagic pancreatitis
Hyperglycemia (low insulin production)

96

Anti-inflammatory drugs used in chemotherapy:
Prednisone/Prednisolone

Glucocorticoid with broad anti-inflammatory effects:

97

******Anti-inflammatory drugs used in chemotherapy:
Piroxicam
DOC for...

transitional cell carcinomas in dogs
---maybe beneficial for SCC, TVT and mammary adenocarcinoma.
Transitional cell carcinoma****** Plus gencidabean******

98

Anti-inflammatory drugs used in chemotherapy:
Piroxicam
P. Dynamics:

Non-specific cyclooxygenase inhibitor

*Help overcome the cancer by reducing the negative inflammation going on

99

Anti-inflammatory drugs used in chemotherapy:
Piroxicam
P. kinetics:

100% BA
Confined mostly to interstitial space
metabolized in the liver
eliminated in the urine

100

******Anti-inflammatory drugs used in chemotherapy:
Piroxicam
Adverse effects:

GI ulceration and renal papillary necrosis
TI is low (severe effects at 3x treatment dose)******

101

Prednisone and piroxicam related to the cell cycle..

Are cell cycle independent!

102

What antineoplastic drugs block..
Sustaining proliferative signaling?

Receptor tyrosine kinase inhibitors.

103

What antineoplastic drugs block..
Deregulating cellular energetics..

Asparaginase

104

What antineoplastic drugs block..
Resisting cell death?

Alkylating agents
Antrhacyclines
Pyrimidine analogs
Microtubule agents

105

What antineoplastic drugs block..
Tumor promoting inflammation?

Prednisone and Piroxicam