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Flashcards in Cancer Drugs Deck (128):
1

List the subclasses of alkylating agents.

Nitrogen Mustards
Alkylsulfonates
Nitrosoureas
(Below drugs are partly aklylators)
Platinum Drugs (cisplatin)
Dacarbazine (a triazene)
Procarbazine (a hydrazine)

2

List the Nitrogen Mustards. (and their common clinical uses)

Cyclophosphamide (non-Hodgkin's Lymphoma, breast/ovarian cancers, neuroblastoma)
Mechlorethamine (Hodgkin's lymphoma)

3

What is the MOA of Nitrogen Mustards?

Alkylate DNA at N7 guanine --> prevent DNA replication through abnormal base pairing, breakage through guanine excision, cross-linking

4

What are the mechanisms of resistance to Nitrogen Mustards ?

DNA repair, decreased drug permeability, and production of trapping agents such as thiols

5

LIst toxicities of Cyclophosphamide.

Expected: GI distress, myelosuppression, alopecia
Other: renal/urotoxic (hemorrhagic cystitis), cardiac dysfunciton, pulmonary toxicity, increased ADH secretion

6

List toxicities of Mechlorethamine.

GI distress, myelosuppression, alopecia, sterility

*also it is a VESICANT (causes blistering)

7

What drug is taken with Mesna? Why?

Cyclophosphamide to protect against acrolein (breakdown product during hepatic CYP450 mediated biotransformation of drug)

8

What is the consequence of acrolein?

causes renal (tubular acidosis, proximal damage, malreabsorption) and urotoxicity/bladder tumors (hemorrhagic cystits*)

9

What are the methods of resistance to cyclophosphamide?

DNA repair enzyme upregulation

10

What type of cells are affected by nitrogen mustard?

affects replicating cells (late G1-S)

11

List the alkyl sulfonates. What is its major us?

Busulfan (in chronic myelogenous leukemia)

12

What are the adverse effects of busulfan?

adrenal insufficiency, lung fibrosis, skin pigmentation

13

What is the ROA of nitrogen mustards?

oral, if available

14

What is the MOA of Busulfan?

Alkylate DNA, prevent DNA replication

15

What is the ROA of busulfan? How does it act in aqueous solution?

oral or IV
Spontaneous hydrolysis in aqueous solution --> liberates active methane sulfates

16

List examples of Nitrosoureas.

Carmustine (BCNU)
Lomustine (CCNU)

17

What is the MOA of Carmustine (BCNU)?

Alkylate DNA, prevent replication/ decomposition products carbomolyate proteins: inhibit DNA repair

18

True or false Nitrosoureas can access BBB.

True- lipophilic, nonionized--> crosses BBB (so useful for brain tumors)

19

List the platinum drugs? What are their common uses?

cisplatin (testicular carcinoma or cancer of bladder, lung, and ovary)
carboplatin (same as cisplatin)
oxaliplatin (advanced colon cancer)

20

What is the MOA of Lomustine (CCNU)?

Alkylate DNA, producing intra- or inter-strand crosslinks that prevent DNA replication

21

What are the toxicities located with cisplatin?

GI distress, mild hematoxicity, nephrotoxic and neurotoxic (peripheral neutopathy and acoustic nerve damage)

22

What are the toxicities located with carboplatin?

Less renal toxicity and less peripheral neuropathy and tinnitius than Cisplatin, thrombocytopenia (greater myelosuppressant actions)

23

What are the toxicities located with oxaliplatin?

dose limiting neurotoxicity

24

What is the system of elimination with platinum drugs?

renal elimination

25

What toxicities are associated with Carmustine (BCNU)?

Hepatic "veno-occlusive disease", CNS (seizures, dementia), pulm fibrosis, endocrine dysfunc, thrombocytopenia, leukopenia

26

What toxicities are associated with Lomustine (CCNU)?

CNS (seizures, dementia), pulm fibrosis, endocrine dysfunc, thrombocytopenia, leukopenia

27

What system metabolizes Nitrosoureas? What is its ROA?

hepatic metabolism
Parenteral

28

What is the toxicity associated with dacarbazine?

Alopecia, skin rash, GI distress, myelosuppression, phototoxicity, and flulike syndrome

29

What is the MOA of procarbazine?

Reactive agent that forms hydrogen peroxide, which generates free radicals and causes DNA strand scission

30

What are the toxicities associated with procarbazine?

Disulfiram-like effect, leukopenia, GI irritation, CNS dysfunction, peripheral neuropathy, skin reactions

Inhibits MAO (and other enzymes

31

What is the common use of procarbazine?

Hodgkin's lymphoma

32

What method of elimination is used for procarbazine?

hepatic metabolism

33

What is the MOA of platinum drugs?

Alkylated DNA at N7 guanine after activation in water. Produced intrastrand G-A cross-links. Interrupts replication and transcription.

34

What are methods of resistance to cisplatin?

glutathione (traps alkylating agents)

35

What platinum drug is associated with development of AML (4yr after treament)?

cisplatin

36

What platinum drug is associated with break and miscoding--> p53 activation and induction of apoptosis?

cisplatin

37

True or false carboplatin and oxaliplatin are taken ONLY orally.

FALSE: taken ONLY IV

38

What is the MOA of dacarbazine?

Metabolically activated DNA methylating agent (on O6 guanine)

39

What are mechanisms of resistance to dacarbazine?

Removal of methyl groups from O6-guanine by AGT

40

True or false: procarbazine can penetrate CSF.

TRUE!! orally active and can penetrate most tissues

41

True or false: alkylating agents are CCNS drugs.

TRUE!

42

Antimetabolites are antagonists of what compounds?

Folic acid
Purines
Pyrimidines

43

Name a folic acid antimetabolite.

Methotrexate

44

Name the purine antimetabolites.

mercaptopurine
thioguanine

45

Name a pyramidine antimetabolites.

fluorouracil, cytarabine, gemcitabine

46

True or false: antimetabolites are CCNS drugs.

FALSE: they are CCS drugs acting primarily in the S phase of the cell cycle

47

Other than cytotoxic effects on neoplastic cells, what is another function of antimetabolites?

immunosuppressants

48

What is the MOA of methotrexate. What compound is formed that is important for its action?

inhibits dihydrofolate reductase leading to decrease in synthesis of thymidylate, purine nucleotides, and amino acids (interferes with nucleic acid and protein metabolism)

*forms polyglutamate derivatives

49

What are the mechanisms of resistance to methotrexate?

-decreased drug accumulation
-changes in drug sensitivity/activity of dihydrofolate reductase
-decreased formation of polyglutamates

50

What is the ROA of methotrexate?

oral or IV

51

Methotrexate is poorly distributed to what tissue?

CNS

52

True or false: methotrexate is metabolized by the liver.

FALSE: methotrexate is NOT metabolized and it is cleared by RENAL function

53

When taking methotrexate, what is important to do?

stay well hydrated, in order to prevent crystallization of renal tubules

54

Methotrexate is used for what cancers?

choriocarcinoma, acute leukemias, etc.

55

Methotrexate has what uses outside of cancer?

Rhematoid arthritis psoriasis
Abortifacient in ectopic pregnancy

56

What are the toxicities associated with methotrexate?

Common: bone marrow suppression, toxic to skin and GI mucosa
Long-term: hepatotoxicity and pulmonary infiltrates/fibrosis

57

What is "leucovorin rescue"?

administration of folinic acid in order to reduce the toxic effects of methotrexate on normal cells

58

What is the MOA of purine antimetabolites (mercaptopurine and thioguanine)?

Activated by hypoxanthine-guanine phosphoribosyltransferases (HGPRTases) to toxic nucleotides that inhibit several enzymes involved in purine metabolism

59

What are methods or resistance to purine antimetabolites?

decrease activity of HGPRTase (activation)
increase activity of alkaline phosphatases (inactivation)

60

What is the DDI with allopurinol and mercaptopurine?

6-MP is metabolically converted in 1 of 3 ways, 1 of which is to thiouric acid (Allopurinol blocks this pathway and can cause drug toxicity)

61

What are the main uses for purine antimetabolites?

acute leukemias and chronic myelocytic leukemia

62

What are the toxicities associated with purine antimetabolites?

-bone marrow suppression (dose limiting)
-hepatic dysfunction (cholestasis, jaundice, necrosis)

63

What is the MOA of 5-fluorouracil?

Inhibition of Thymidylate Synthase, DNA synthesis inhibition via "thymineless death," gets incorporated into DNA -> inhibition of synthesis & function, interferes w/ mRNA translation

64

What are resistance mechanisms against 5-fluorouracil?

decreased activation of 5-FU
Increased thymidylate synthase activity
reduced drug sensitivity to this enzyme

65

What is the ROA of fluorouracil?

IV- widely distributed, even to CSF
topically- for some keratoses/superficial basal cell carcinomas

66

How is fluorouracil eliminated?

mainly by metabolism

67

What are the uses of fluorouracil?

bladder, breast, colon, head/neck, liver, and ovarian cancers
(also topical use)

68

What pyramidine antimetabolite is MOST specific for the S phase of the cell cycle?

cytarabine

69

What is the MOA of cytarabine?

Converted to ARA-CTP, which inhibits DNA polymerase-alpha

70

What are the resistance mechanisms against cytarabine?

decreased uptake
decreased conversion to ARA-CTP

71

What is the MOA of gemcitabine?

converted to active diphosphate and triphosphate nucleotide forms that inhibits ribonucleotide reductase and diminished pool of DNTs required for DNA synthesis.

also can be incorporated into DNA and cause chain termination

72

What is the method of elimination of gemcitabine?

metabolism mainly

73

What is the clinical use of gemcitabine?

pancreatic cancer*
non-small cell lung cancer
bladder cancer
non-Hodgkin's lymphoma

74

What are the toxicities of gemcitabine?

neutropenia
pulmonary toxicity

75

True or false: plant alkaloids are CCNS drugs.

FALSE: CCS drugs that act in various specific phases of the cell cycle

76

List the subtypes of plant alkaloids.

Vinca Alkaloids
Podophyllotoxins
Camptothecins
Taxanes

77

What is the phase favored by Vinca Alkaloids?

M phase

78

LIst the vinca alkaloids.

vinblastine
vincristine
vinorelbine

79

What is the MOA of Vinca Alkaloids?

Bind to beta-tubulin: prevent microtubule polymerization (and mitotic spindle formation)

80

What are mechanisms of resistance against Vinca Alkaloids?

increased efflux of drugs via membrane drug transporters

81

What is the ROA of vinca alkaloids?

parenterally (can penetrate most tissues but CSF)

82

What is the elimination mechanism of vinca alkaloids?

biliary excretion

83

What are the toxicities of vinca alkaloids?

vinblastine/vinorelbine: GI distress, alopecia, bone marrow suppression
vincristine: NO myelosuppression but DOES cause neurotoxic actions (areflexia, peripher neuropathy, paralytic ileus)

84

What is the phase favored by Podophyllotoxins?

late S to early G2 phases of cell cycle

85

LIst the Podophyllotoxins.

etoposide
teniposide (analog)

86

What is the MOA of Podophyllotoxins?

-Form complex w/ topoisomerase II & DNA to disrupt repair of dsDNA breaks
-Inhibits mitochondrial electron transport

87

What is the ROA of Podophyllotoxins?

oral administration

88

What is the mechanism of elimination of Podophyllotoxins?

renal elimination

89

What are the toxicities associated with Podophyllotoxins?

GI irritants
Alopecia
Bone marrow suppression

90

List the camptothecins.

topotecan
Irinotecan

91

What is the MOA of camptothecins?

Inhibit DNA topoisomerase I and damage DNA by inhibiting an enzyme that cuts and relegates single DNA strands during normal DNA repair process

92

Which camptothecin is a prodrug that is converted to active metabolite in liver?

irinotecan

93

True or false: all camptothecins are eliminated through the renal system.

False- topotecan is eliminated renally and irinotecan is eliminated in bile and feces

94

What toxicities are associated with camptothecin?

myelosuppression and diarrhea

95

List the taxanes.

paclitaxel
docetaxel

96

What is the MOA of taxanes?

interfere with mitotic spindle and prevent microtubule DISASSEMBLY into tubulin monomers (different than alkaloids)

97

What is the ROA of taxanes?

oral

98

What are the most common uses of taxanes?

advanced breast and ovarian cancers

99

What are the toxicities associated with paclitaxel?

neutropenia
thrombocytopenia
peripheral neuropathy
possible hypersensitivity reaction during infusion

100

What are the toxicities associated with docetaxel?

neurotoxicity
bone marrow depression

101

List the antibiotics used in cancer treatment.

Doxorubicin
Daunorubucin
Bleomycin
Dactinomycin
Mitomycin

102

True or false: Doxorubicin and Daunorubucin are CCNS drugs?

TRUE!

103

What is the MOA of Doxorubicin and Daunorubucin?

intercalate between base pairs, inhibit topoisomerase II, and generate free radicals.

Block RNA/DNA synthesis, cause DNA strand scission, membrane disruption

104

What is the ROA and excretion mechanism of Doxorubicin and Daunorubucin?

ROA: IV
Elimination: liver metabolism and excreted in bile and urine

105

What are the toxicities associated with Doxorubicin and Daunorubucin?

CARDIOTOXICITY (possibility of arrhythmias, cardiomyopathy, CHF)
bone marrow suppression
GI distress
severe alopecia

106

What may help to alleviate the cardiotoxicity of Doxorubicin and Daunorubucin?

dexrazoxane (inhibitor of free-radical administration)

107

True or False: Bleomycin is a CCNS drug?

FALSE: it is a CCS drug active in G2 phase of cell cycle

108

What is the MOA of Bleomycin?

Glycopeptides that generate free radicals which bind to DNA and cause strand breaks--inhibiting DNA synthesis

109

What is the ROA and excretion mechanism of Bleomycin?

ROA: parenterally
Inactivated: aminopeptidases
Clearance: renal clearance

110

What are the toxicities associated with bleomycin?

Pulmonary dysfunction (pneumonitis, fibrosis)
Hypersensitivity (chills, fever, anaphylaxis)
Mucocutaneous reactions (blisters, alopecia, hyperkeratosis)

111

True or false: Dactinomycin is a CCNS drug.

TRUE

112

What is the MOA of Dactinomycin?

binds to dsDNA and inhibits DNA-dependent RNA synthesis

113

What is the ROA and excretion mechanism of Dactinomycin?

ROA: parenterally
Elimination of both intact and metabolites through bile

114

What are the toxicities associated with Dactinomycin?

bone marrow suppression
skin reactions
GI irritation

115

True or false: Mitomycin is a CCNS drug.

TRUE

116

What is the MOA of Mitomycin?

metabolized by liver enzymes to form alkylating agent that cross-links DNA

117

What is the ROA and excretion mechanism of mitomycin?

ROA: IV
Excretion: hepatic metabolism

118

What are the toxicities associated with mitomycin?

severe myelosuppression
Toxic to heart, liver, lung, kidney

119

True or false: anticancer drugs obey 0 order kinetics.

FALSE: they obey the log kill hypothesis (1st order kinetics)

120

What are the 4 cardinal principles of combination chemotherapy?

1) Activity
2) Different MOAs
3) No/Minimal cross-resistance
4) Different pattern of toxicity

121

What two classes would you NEVER take together due to additive neurotoxicity?

vinca alkyloids and taxanes
cause "stocking glove syndrome"

122

What cancer drug has adverse effects on the kidney?

cisplatin

123

What can be taken BEFORE fluorouracil to make 5-FU more affective?

Leucovorin will get cells to start dividing rapidly, so more cells will be in the synthesis phase (where fluorouracil works!)

124

What can be taken with mercaptopurine to increase the toxicity of it?

allopurinol

125

What should be taken with cisplatin for cytoprotection?

amifostine

126

What drugs can be administered to protect against tumor lysis syndrome?

Allopurinol (blocks xanthine oxidase at two steps)
Rasburicase (stimulates urate oxidase to change uric acid into allantoin

127

What is tumor lysis syndrome?

if too many tumor cells lyse at the same time, lots of cellular contents are put into the blood and are shunted to the kidney to be excreted (VERY nephrotoxic)

128

P-gp overexpression is common in tumors and causes what?

P-glycoprotein is one of the components of the BBB that renders many drugs unable to pass. If this is upregulated in tumors, it will cause drug resistance.