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SBL Final > Cancer Pharmacology (Part 2 of 2) > Flashcards

Cancer Pharmacology (Part 2 of 2) Flashcards

1
Q

What are the important alkylating agents we talked about? (broad- 3)

A

nitrogen mustards, alkyl sulfonate, and platinum coordination complexes

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2
Q

what are two important nitrogen mustard drugs?

A

cyclophosphamide and ifosfamide

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3
Q

what is an important alkyl sulfonate drug?

A

busulfan

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4
Q

what is an important platinum coordination complex drug?

A

cisplatin

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5
Q

there are five major types of alkylating agents, what are they?

A

nitrogen mustards, nitrosoureas, alkyl sulfonates, methylhydrazine derivatives, and Triazines

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6
Q

what is an example of a nitrosoureas?

A

carmustine

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7
Q

what is an example of methylhydrazine derivatives?

A

procarbazine

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8
Q

what is an example of triazines?

A

dacarbazine

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9
Q

what is the most widely used alkylating agent and also one of the most emetogenic agents?

A

the nitrogen mustard- cyclophosphamide

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10
Q

are alkylating agents cell cycle specific or nonspecific?

A

cell cycle nonspecific

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11
Q

what is the mechanism of action of alkylating agents?

A

they form covalent linkages with DNA

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12
Q

specifically, how does cyclophosphamide work?

A

it targets the guanines and makes these cross links either within the same strand or across the strand- so the helicase coming down unwinding DNA can’t go any further once it hits this cross link and that leads to cell death

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13
Q

what does cyclophosphamide need to be activated by?

A

cytochrome p450

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14
Q

what is one of the most common atypical adverse effects of cyclophosphamide?

A

hemorrhagic cystitis

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15
Q

what causes the hemorrhagic cystitis in patients receiving cyclophosphamide?

A

it is due to the toxic metabolite Acrolein

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16
Q

what is the rescue agents that can prevent hemorrhagic cystitis caused by acrolein?

A

Mesna- it inactivates acrolein and is used for prophylaxis of chemotherapy induced cystitis

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17
Q

systemic toxicities are what?

A

dose related

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18
Q

oral administration of alkylating agents is of great clinical benefit because why?

A

you aren’t going to cause the injection related events such as direct vesicant effects and tissue damage at site of injection

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19
Q

many alkylating agents produce acute toxicity such as what? and how can you treat this?

A

such as nausea and vomiting; pretreat with serotonin antagonist

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20
Q

what are 2 atypical adverse effects of cisplatin?

A

renal tubular damage and ototoxicity

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21
Q

what is an atypical adverse effect of Busulfan?

A

pulmonary fibrosis

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22
Q

what are antimetabolites?

A

they are structural analogs to compounds necessary for cell proliferation; they block or subvert pathways that are involved in or lead to cell replication (nucleotide and nucleic acid synthesis)

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23
Q

are antimetabolites cell cycle specific or nonspecific?

A

cell cycle specific- they block formation of the building blocks of DNA and DNA is only built during S phase

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24
Q

what are the 3 main categories of antimetabolites?

A

folic acid analogs, pyrimidine analogs, and purine analogs

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25
Q

what is an example of a folic acid analog?

A

methotrexate

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26
Q

what is an example of a pyrimidine analog?

A

5-fluorouracil

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27
Q

what is an example of a purine analog?

A

6-mercaptopurine (6-MP)

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28
Q

what is the mechanism of action of methotrexate?

A

it inhibits dihydrofolate reductase, which means that this pathway cannot be competed to form dTMP–> dTTP–> DNA

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29
Q

besides the treatment of cancer, what else can methotrexate be used for?

A

RA and psoriasis

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30
Q

what is one of the atypical adverse effects of high dose methotrexate?

A

mucosal ulceration

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31
Q

what is a rescue agent for methotrexate and how does it work?

A

leucovorin; administration of the reduced folate leucovorin at a non-high dose–> the healthy cells will accept it but the cancer cells will not

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32
Q

what is the mechanism of action of flurouracil?

A

5-fluorouracil blocks the thymidylate synthetase–> so we can’t make dTMP–> dTTP–> DNA

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33
Q

what was the example fo a drug-drug interaction affecting bioavailability that we talked about?

A

mercaptopurine and allopurinol

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34
Q

what are the general characteristics of 6-MP?

A

it is inactive in its parent form

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35
Q

what metabolizes 6-MP?

A

HGPRT

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36
Q

what is the effect of xanthine oxidase on 6-MP?

A

it metabolizes it to the inactive metabolite 6-thiouric acid (first pass effect)

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37
Q

what is a drug that is a xanthine oxidase inhibitor?

A

allopurinol

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38
Q

simultaneous administration of allopurinol and PO 6-MP results in what?

A

increased levels of 6-MP and increased toxicity

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39
Q

how can you still use allopurinol and 6-MP together without toxic effects?

A

you need to reduce oral 6-MP dose by 50-75%; IV dose is unaffected

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40
Q

antimetabolites are cell cycle specific for what phase?

A

s-phase

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41
Q

what is the toxicity like of antimetabolites?

A

relatively little acute toxicity after an initial dose

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42
Q

what are common routes of administration of antimetabolites?

A

oral, intravenous, intrathecal (methotrexate)

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43
Q

what common toxicities associated with antimetabolites? (8)

A

diarrhea, myelosuppression, nausea, vomiting, immunosuppression, thrombocytopenia, leukopenia, and hepatotoxicity

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44
Q

what are 6 broad classes of natural antineoplastic agents?

A

vinca alkaloids, taxanes, epipodophyllotoxins, antibiotics, anthracenedione, and enzymes

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45
Q

what are 2 examples of vinca alkaloids?

A

vinblastine and vincristine

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46
Q

what is an example of a taxane?

A

paclitaxel

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47
Q

what is an example of epipodophyllotoxins?

A

etoposide

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48
Q

what is an example of a natural antineoplastic antibiotic?

A

doxorubicin

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49
Q

what is an example of an anthracenedione?

A

bleomycin

50
Q

what is an example of a natural antineoplastic enzyme?

A

l-asparaginase

51
Q

where do vinca alkaloids come from?

A

madagascar periwinkle

52
Q

what is the MOA of vinca alkaloids (vinblastine and vincristine)?

A

they bind to beta-tubulin and inhibit microtubule assembly –> they cause depolarization; they destabalize microtubule formation

53
Q

are vinca alkaloids cell cycle specific or nonspecific?

A

cell cycle specific (mitosis inhibition so M-phase specific)

54
Q

what are the common adverse effects of vinca alkaloids?

A

alopecia and bone marrow depression

55
Q

what does vinblastine cause?

A

myelosuppression to a greater extent than vincristine

56
Q

what does vincristine cause?

A

cumulative neurological toxicities (numbness and tingling of the extremities, loss of DTRs, motor weakness) compared to vinblastine

57
Q

what is the main difference between vinca alkaloids and taxanes?

A

vinca alkaloids destabilize microtubule formation and taxanes stabilize microtubule formation

58
Q

what is the MOA of taxanes?

A

they bind to beta-tubulin and stabilize microtubule formation

59
Q

is taxane cell cycle specific or nonspecific?

A

cell cycle specific- mitosis inhibition- so specific to M phase

60
Q

what are two examples of taxanes?

A

paclitaxela dn docetaxel

61
Q

what are the adverse effects of paclitaxel?

A

hypersensitivity reactions in hands and toes, change in taste

62
Q

what are the characteristics of docetaxel?

A

greater cellular uptake and retained intracellularly longer than paclitaxel, leading to smaller dose and less side effects

63
Q

what are the side effects of docetaxel?

A

hypersensitivity, neutropenia, and hair loss

64
Q

what was the traditional use of taxanes used for?

A

breast cancer

65
Q

inhibition of topoisomerase enzymes causes what?

A

DNA damage and leads to cell death

66
Q

which drugs inhibit topoisomerase I?

A

camptothecins (topotecan and irinotecan)

67
Q

which drugs inhibit topoisomerase II?

A

epipodophyllotoxins and anthracycline antibiotics

68
Q

what are 2 examples of epipodophyllotoxins?

A

etoposide and teniposide

69
Q

what are 2 examples of anthracycline antibiotics?

A

doxorubicin and daunorubicin

70
Q

are topoisomerase inhibitors cell cycle specific or nonspecific?

A

cell cycle specific (primarily S; also G1 and G2)

71
Q

all of the anticancer antibiotics currently in use are products of what?

A

various strains of the soil microbe Streptomyces

72
Q

what are the effects of antitumor antibiotics?

A

mainly on DNA

73
Q

what are 4 broad examples of effective antitumor antibiotic agents?

A

anthracyclines, dactinomycin, bleomycin, and mitomycin

74
Q

what is the MOA of anthracyclines?

A

Topoisomerase II inhibitor and DNA intercalation

75
Q

are anthracyclines cell cycle specific or nonspecific?

A

cell cycle non specific

76
Q

what is super important to remember about anthracyclines (what do they produce)?

A

they produce free radicals, and these free radicals can lead to significant cardiotoxicity

77
Q

cumulative cardiac damage can lead to what?

A

dysrhythmias and heart failure

78
Q

what is the MOA of bleomycin?

A

single and double stranded DNA breaks

79
Q

what is the atypical adverse effect associated with bleomycin?

A

causes significant pulmonary toxicity and usually presents as pneumonitis with cough, dyspnea, and dry inspiratory crackles

80
Q

what is the MOA of dactinomycin?

A

intercalation of DNA

81
Q

what is a specific example of anthracyclines?

A

doxorubicin

82
Q

what are the natural antineogenic agents: enzymes: asparaginase and pegaspargase used for?

A

targeted therapy for acute lymphoblastic leukemia (ALL)

83
Q

ALL tumor cells lack what?

A

the enzyme asparagine synthetase, and because they lack that enzyme they require an exogenous source of L-asparagine

84
Q

what is the MOA of asparaginase and pegaspargase?

A

they hydrolyze circulating L-asparagine into aspartic acid and ammonia, effectively inhibiting protein synthesis

85
Q

are natural antineogenic enzymes: asparaginase and pegaspargase cell cycle specific or non specific?

A

cell cycle specific (G1)

86
Q

what are the adverse side effects associated with asparaginase and pegaspargase?

A

acute hypersensitivity: fever, chills, nausea, vomiting, skin rash, and urticaria

87
Q

what are the delayed toxicities associated with asparaginase and pegaspargase?

A

increased risk of clotting and bleeding, pancreatitis, and CNS toxicity including lethargy, confusion, hallucinations, and coma

88
Q

the t(15;17) translocation creates what fusion protein?

A

PML-RARalpha

89
Q

what does the fusion protein PML-RARalpha inhibit?

A

granulocytic maturation in APL

90
Q

what is an example of a differentiating agent and what is it used for?

A

tretinoin (all-trans-retinoic acid) binds to the PML-RAR alpha fusion protein and anatagonizes (aka blocks) the inhibitory effect on the transcription of target genes

91
Q

what happens after administration of tretinoin (all-trans-retinoic acid)?

A

within 1-2 days the neoplastic promyelocytes begin to differentiate into neutrophils, which rapidly die

92
Q

what are common adverse effects associated with use of tretinoin (all-trans-retinoic acid)?

A

vitamin A toxicity and retinoic acid syndrome

93
Q

what happens when tyrosine kinases are mutated, overexpressed, or structurally altered?

A

they can become potent oncoproteins

94
Q

what antineoplastic agents target intracellular tyrosine kinases?

A

-nibs

95
Q

what antineoplastic agents target extracellular tyrosine kinases?

A

-mabs

96
Q

what is the result from the t(9:22) translocation?

A

the BCR-ABL fusion protein–> CML

97
Q

what can treat CML?

A

imatinib

98
Q

besides inhibiting the ABL tyrosine kinase, what else can imatinib inhibit?

A

the RTKs PDGFR and KIT

99
Q

what is erlotinib and gefitinib?

A

tyrosine kinase domain inhibitors of the EGFR

100
Q

what is erlotinib and gefitnib used for?

A

refractory non-small cell lung cancer, pancreatic cancer

101
Q

what toxicities do erlotinib and gefitnib produce?

A

dermatologic toxicities

102
Q

if patients are diagnosed with a cancer that has a high activity of VEGFR, what can they be treated with?

A

ziv-aflibercept

103
Q

what is ziv-aflibercept?

A

recombinant fusion protein made up of portions of the extracellular domains oh human VEGF receptors 1 and 2 fused to the Fc portion of the human IgG1 molecule–> inhibits VEGFR signaling

104
Q

what is the MOA of growth factor receptor inhibitors?

A

inhibit growth factor receptor signaling

105
Q

what is the MOA of tyrosine kinase inhibitors?

A

inhibit tyrosine kinase activity

106
Q

what is the mechanism of resistance for tyrosine kinase and growth factor receptor inhibitors?

A

point mutations in drug binding sites

107
Q

what are common adverse effects seen with tyrosine kinase and growth factor receptor inhibitors?

A

nausea and vomiting; acneform skin rash and hypersensitivity (allergic reaction)

108
Q

what are biological response modifiers?

A

agents that act indirectly on the immune system to mediate their antitumor effects by enhancing the immunologic response to neoplastic cells

109
Q

what are two examples of biological response modifiers?

A

interferons (interferon-alpha2a and alpha 2b) and interleukin-2

110
Q

what is the effect of interferons?

A

they inhibit cellular growth, alter the state of cellular differentiation, interfere with oncogene expression, alter cell surface antigen expression, increase phagocytic activity of macrophages

111
Q

what adverse effects can interferons cause?

A

bone marrow depression, neutropenia, anemia, renal toxicity, edema, and arrhythmias

112
Q

what is the effect of interleukin-2?

A

it increases the cytotoxic killing by T cells and NK cells

113
Q

what is the major toxicity associated with interleukin-2?

A

capillary leak syndrome

114
Q

what is the MOA of antibodies used to treat neoplastic disorders?

A

the antigen

115
Q

rituximab targets what antigen? and what is this used to treat?

A

CD20; non-hodgkin’s lymphoma

116
Q

what are the most active cytotoxic agents used to treat malignant melanoma?

A

dacarbazine and cisplatin; but the response rate to these agents is low

117
Q

what biological agents are used to treat malignant melanoma?

A

IFN-alpha and interleukin-2

118
Q

what are the target therapies that have been used to treat malignant melanoma based on the genotypic analysis?

A

nivolumab and pembrolizumab

119
Q

what does nivolumab and pembrolizumab target?

A

the BRAF V600E mutation that is present in a large majority of melanomas

120
Q

what three drugs target BRAF directly?

A

vemurafenib, dabrafenib, and encorafenib

SBL Final (21 decks)

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