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CMOD Block 2 > Cancer Drugs > Flashcards

Cancer Drugs Flashcards

1
Q

List the subclasses of alkylating agents.

A 
Nitrogen Mustards
Alkylsulfonates
Nitrosoureas
(Below drugs are partly aklylators)
Platinum Drugs (cisplatin)
Dacarbazine (a triazene)
Procarbazine (a hydrazine)
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2
Q

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

A

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

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3
Q

What is the MOA of Nitrogen Mustards?

A

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

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4
Q

What are the mechanisms of resistance to Nitrogen Mustards ?

A

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

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5
Q

LIst toxicities of Cyclophosphamide.

A

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

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6
Q

List toxicities of Mechlorethamine.

A

GI distress, myelosuppression, alopecia, sterility

*also it is a VESICANT (causes blistering)

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7
Q

What drug is taken with Mesna? Why?

A

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

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8
Q

What is the consequence of acrolein?

A

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

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9
Q

What are the methods of resistance to cyclophosphamide?

A

DNA repair enzyme upregulation

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10
Q

What type of cells are affected by nitrogen mustard?

A

affects replicating cells (late G1-S)

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11
Q

List the alkyl sulfonates. What is its major us?

A

Busulfan (in chronic myelogenous leukemia)

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12
Q

What are the adverse effects of busulfan?

A

adrenal insufficiency, lung fibrosis, skin pigmentation

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13
Q

What is the ROA of nitrogen mustards?

A

oral, if available

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14
Q

What is the MOA of Busulfan?

A

Alkylate DNA, prevent DNA replication

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15
Q

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

A

oral or IV

Spontaneous hydrolysis in aqueous solution –> liberates active methane sulfates

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16
Q

List examples of Nitrosoureas.

A

Carmustine (BCNU)

Lomustine (CCNU)

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17
Q

What is the MOA of Carmustine (BCNU)?

A

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

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18
Q

True or false Nitrosoureas can access BBB.

A

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

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19
Q

List the platinum drugs? What are their common uses?

A

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

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20
Q

What is the MOA of Lomustine (CCNU)?

A

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

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21
Q

What are the toxicities located with cisplatin?

A

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

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22
Q

What are the toxicities located with carboplatin?

A

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

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23
Q

What are the toxicities located with oxaliplatin?

A

dose limiting neurotoxicity

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24
Q

What is the system of elimination with platinum drugs?

A

renal elimination

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25
Q

What toxicities are associated with Carmustine (BCNU)?

A

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

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26
Q

What toxicities are associated with Lomustine (CCNU)?

A

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

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27
Q

What system metabolizes Nitrosoureas? What is its ROA?

A

hepatic metabolism

Parenteral

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28
Q

What is the toxicity associated with dacarbazine?

A

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

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29
Q

What is the MOA of procarbazine?

A

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

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30
Q

What are the toxicities associated with procarbazine?

A

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

Inhibits MAO (and other enzymes

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31
Q

What is the common use of procarbazine?

A

Hodgkin’s lymphoma

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32
Q

What method of elimination is used for procarbazine?

A

hepatic metabolism

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33
Q

What is the MOA of platinum drugs?

A

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

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34
Q

What are methods of resistance to cisplatin?

A

glutathione (traps alkylating agents)

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35
Q

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

A

cisplatin

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36
Q

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

A

cisplatin

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37
Q

True or false carboplatin and oxaliplatin are taken ONLY orally.

A

FALSE: taken ONLY IV

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38
Q

What is the MOA of dacarbazine?

A

Metabolically activated DNA methylating agent (on O6 guanine)

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39
Q

What are mechanisms of resistance to dacarbazine?

A

Removal of methyl groups from O6-guanine by AGT

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40
Q

True or false: procarbazine can penetrate CSF.

A

TRUE!! orally active and can penetrate most tissues

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41
Q

True or false: alkylating agents are CCNS drugs.

A

TRUE!

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42
Q

Antimetabolites are antagonists of what compounds?

A

Folic acid
Purines
Pyrimidines

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43
Q

Name a folic acid antimetabolite.

A

Methotrexate

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44
Q

Name the purine antimetabolites.

A

mercaptopurine

thioguanine

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45
Q

Name a pyramidine antimetabolites.

A

fluorouracil, cytarabine, gemcitabine

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46
Q

True or false: antimetabolites are CCNS drugs.

A

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

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47
Q

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

A

immunosuppressants

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48
Q

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

A

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

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49
Q

What are the mechanisms of resistance to methotrexate?

A
  • decreased drug accumulation
  • changes in drug sensitivity/activity of dihydrofolate reductase
  • decreased formation of polyglutamates
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50
Q

What is the ROA of methotrexate?

A

oral or IV

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51
Q

Methotrexate is poorly distributed to what tissue?

A

CNS

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52
Q

True or false: methotrexate is metabolized by the liver.

A

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

53
Q

When taking methotrexate, what is important to do?

A

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

54
Q

Methotrexate is used for what cancers?

A

choriocarcinoma, acute leukemias, etc.

55
Q

Methotrexate has what uses outside of cancer?

A

Rhematoid arthritis psoriasis

Abortifacient in ectopic pregnancy

56
Q

What are the toxicities associated with methotrexate?

A

Common: bone marrow suppression, toxic to skin and GI mucosa

Long-term: hepatotoxicity and pulmonary infiltrates/fibrosis

57
Q

What is “leucovorin rescue”?

A

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

58
Q

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

A

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

59
Q

What are methods or resistance to purine antimetabolites?

A

decrease activity of HGPRTase (activation)

increase activity of alkaline phosphatases (inactivation)

60
Q

What is the DDI with allopurinol and mercaptopurine?

A

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
Q

What are the main uses for purine antimetabolites?

A

acute leukemias and chronic myelocytic leukemia

62
Q

What are the toxicities associated with purine antimetabolites?

A
  • bone marrow suppression (dose limiting)

- hepatic dysfunction (cholestasis, jaundice, necrosis)

63
Q

What is the MOA of 5-fluorouracil?

A

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

64
Q

What are resistance mechanisms against 5-fluorouracil?

A

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

65
Q

What is the ROA of fluorouracil?

A

IV- widely distributed, even to CSF

topically- for some keratoses/superficial basal cell carcinomas

66
Q

How is fluorouracil eliminated?

A

mainly by metabolism

67
Q

What are the uses of fluorouracil?

A

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

68
Q

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

A

cytarabine

69
Q

What is the MOA of cytarabine?

A

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

70
Q

What are the resistance mechanisms against cytarabine?

A

decreased uptake

decreased conversion to ARA-CTP

71
Q

What is the MOA of gemcitabine?

A

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
Q

What is the method of elimination of gemcitabine?

A

metabolism mainly

73
Q

What is the clinical use of gemcitabine?

A

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

74
Q

What are the toxicities of gemcitabine?

A

neutropenia

pulmonary toxicity

75
Q

True or false: plant alkaloids are CCNS drugs.

A

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

76
Q

List the subtypes of plant alkaloids.

A

Vinca Alkaloids
Podophyllotoxins
Camptothecins
Taxanes

77
Q

What is the phase favored by Vinca Alkaloids?

A

M phase

78
Q

LIst the vinca alkaloids.

A

vinblastine
vincristine
vinorelbine

79
Q

What is the MOA of Vinca Alkaloids?

A

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

80
Q

What are mechanisms of resistance against Vinca Alkaloids?

A

increased efflux of drugs via membrane drug transporters

81
Q

What is the ROA of vinca alkaloids?

A

parenterally (can penetrate most tissues but CSF)

82
Q

What is the elimination mechanism of vinca alkaloids?

A

biliary excretion

83
Q

What are the toxicities of vinca alkaloids?

A

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

84
Q

What is the phase favored by Podophyllotoxins?

A

late S to early G2 phases of cell cycle

85
Q

LIst the Podophyllotoxins.

A

etoposide

teniposide (analog)

86
Q

What is the MOA of Podophyllotoxins?

A
  • Form complex w/ topoisomerase II & DNA to disrupt repair of dsDNA breaks
  • Inhibits mitochondrial electron transport
87
Q

What is the ROA of Podophyllotoxins?

A

oral administration

88
Q

What is the mechanism of elimination of Podophyllotoxins?

A

renal elimination

89
Q

What are the toxicities associated with Podophyllotoxins?

A

GI irritants
Alopecia
Bone marrow suppression

90
Q

List the camptothecins.

A

topotecan

Irinotecan

91
Q

What is the MOA of camptothecins?

A

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

92
Q

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

A

irinotecan

93
Q

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

A

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

94
Q

What toxicities are associated with camptothecin?

A

myelosuppression and diarrhea

95
Q

List the taxanes.

A

paclitaxel

docetaxel

96
Q

What is the MOA of taxanes?

A

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

97
Q

What is the ROA of taxanes?

A

oral

98
Q

What are the most common uses of taxanes?

A

advanced breast and ovarian cancers

99
Q

What are the toxicities associated with paclitaxel?

A

neutropenia
thrombocytopenia
peripheral neuropathy
possible hypersensitivity reaction during infusion

100
Q

What are the toxicities associated with docetaxel?

A

neurotoxicity

bone marrow depression

101
Q

List the antibiotics used in cancer treatment.

A 
Doxorubicin
Daunorubucin
Bleomycin
Dactinomycin
Mitomycin
102
Q

True or false: Doxorubicin and Daunorubucin are CCNS drugs?

A

TRUE!

103
Q

What is the MOA of Doxorubicin and Daunorubucin?

A

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

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

104
Q

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

A

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

105
Q

What are the toxicities associated with Doxorubicin and Daunorubucin?

A

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

106
Q

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

A

dexrazoxane (inhibitor of free-radical administration)

107
Q

True or False: Bleomycin is a CCNS drug?

A

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

108
Q

What is the MOA of Bleomycin?

A

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

109
Q

What is the ROA and excretion mechanism of Bleomycin?

A

ROA: parenterally
Inactivated: aminopeptidases
Clearance: renal clearance

110
Q

What are the toxicities associated with bleomycin?

A 
Pulmonary dysfunction (pneumonitis, fibrosis)
Hypersensitivity (chills, fever, anaphylaxis)
Mucocutaneous reactions (blisters, alopecia, hyperkeratosis)
111
Q

True or false: Dactinomycin is a CCNS drug.

A

TRUE

112
Q

What is the MOA of Dactinomycin?

A

binds to dsDNA and inhibits DNA-dependent RNA synthesis

113
Q

What is the ROA and excretion mechanism of Dactinomycin?

A

ROA: parenterally

Elimination of both intact and metabolites through bile

114
Q

What are the toxicities associated with Dactinomycin?

A

bone marrow suppression
skin reactions
GI irritation

115
Q

True or false: Mitomycin is a CCNS drug.

A

TRUE

116
Q

What is the MOA of Mitomycin?

A

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

117
Q

What is the ROA and excretion mechanism of mitomycin?

A

ROA: IV
Excretion: hepatic metabolism

118
Q

What are the toxicities associated with mitomycin?

A

severe myelosuppression

Toxic to heart, liver, lung, kidney

119
Q

True or false: anticancer drugs obey 0 order kinetics.

A

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

120
Q

What are the 4 cardinal principles of combination chemotherapy?

A

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

121
Q

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

A

vinca alkyloids and taxanes

cause “stocking glove syndrome”

122
Q

What cancer drug has adverse effects on the kidney?

A

cisplatin

123
Q

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

A

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

124
Q

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

A

allopurinol

125
Q

What should be taken with cisplatin for cytoprotection?

A

amifostine

126
Q

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

A

Allopurinol (blocks xanthine oxidase at two steps)

Rasburicase (stimulates urate oxidase to change uric acid into allantoin

127
Q

What is tumor lysis syndrome?

A

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
Q

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

A

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.

CMOD Block 2 (11 decks)

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