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IBI Test 3 > B3.042,B3.079 Anticancer Chemotherapy > Flashcards

B3.042,B3.079 Anticancer Chemotherapy Flashcards

1
Q

describe selective toxicity

A

targeting a pathogen rather than the host
goal of chemotherapy
relative, not usually absolute

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2
Q

how is selective toxicity generally achieved in cancer treatment?

A

target is more essential in pathogen than in host

  • greater utilization in tumor than in host
  • the least selective path
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3
Q

what are the 5 general characteristics of tumor cells

A 
excessive/inappropriate growth
diminished apoptosis
loss of differentiation
invasive
metastatic
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4
Q

why is early detection of cancer key?

A

symptoms appear very close in the timeline of pathogenesis to death

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5
Q

what is the main goal of chemo?

A

to kill all tumor cells with the potential for proliferation

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6
Q

what are determinants of success in cancer treatment

A

efficacy, frequency, and duration

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7
Q

adjuvant

A

chemotherapy following surgery or radiation

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8
Q

neoadjuvant

A

chemotherapy before surgery or radiation

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9
Q

what % of cancers can be cured using multi-modality therapy?

A

50%

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10
Q

what % of cancers can be cured with chemo alone?

A

17%

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11
Q

describe the relationship between the cell cycle and chemotherapy

A

certain anti cancer drugs are only effective during specific stages of the cell cycle
cell cycle specific:
-antimetabolites
-topoisomerase inhibitors
-microtubule poisons
certain anti cancer drugs are effective during any stage of the cell cycle
cell cycle non specific:
-alkylating agents
-antitumor antibiotics
-still most effective against rapidly cycling cells

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12
Q

why might drugs be less effective on a cell in the G0 phase?

A

drugs induce damage on DNA
race between repair and replication
if in G0, the cell has more time to repair the damage

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13
Q

why is targeting tumor cells’ high proliferative potential a problem?

A

normal cell populations can also have this high proliferative potential
-key factor in adverse effects

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14
Q

what are normal cell populations that have high proliferative potentials

A

BM
epithelial cells
immune system
hair follicles

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15
Q

what do most effective anticancer drugs activate?

A

apoptosis

does not occur in the absence of functional p53

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16
Q

what are some generalized acute effects of chemo?

A

nausea and vomiting

can cause dehydration, malnutrition, and metabolic disorders

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17
Q

how can acute effects of chemo be treated?

A

antimetics
-5-HT3 antagonists (Odansetron)
-Phenothiazines (sedatives)
30% unaffected by antimetics

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18
Q

what are some delayed effects of chemo on bone marrow?

A

myelosuppression

  • usually leukopenia (neutropenia) and thrombocytopenia
  • risk of bleeding, infection
  • pancytopenia
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19
Q

how can delayed effects of chemo on bone marrow be treated?

A

GM-CSF (granulocyte macrophage colony stimulating factor)
platelet transfusions
EPO (erythropoietin)

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20
Q

what are some other delayed effects of chemo?

A 
GI effects
-diarrhea, mucositis, stomatitis
prolonged myelosuppression
alopecia
neuropathies
hand and foot syndrome (neuropathy + hemodynamic changes)
"signature" adverse effects
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21
Q

what is primary resistance

A

tumor cells initially not sensitive to a given drug (test by in vitro sensitivity or tumor genotype)

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22
Q

what is secondary resistance

A

tumor cells develop resistance during therapy
amplification/alteration of targets
enhanced repair
changes in permeability

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23
Q

what is P-glycoprotein?

A

Pgp, MDR-1
efflux pump that can export multiple calluses of anti-cancer drugs
-antimetabolites, antibiotics, alkaloids, et al.

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24
Q

what are the major classes of antineoplastic drugs

A 
alkylating agents
antimetabolites
antitumor antibiotics
microtubule poisons
topoisomerase inhibitors
targeted therapies* (not cytotoxic)
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25
Q

what are the 4 main classes of targeted therapies

A

hormones/hormone modulators
biologicals
tyrosine kinase inhibitors
other

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26
Q

what is the generalized benefit of targeted therapies

A

more selective for targeting tumor

fewer adverse effects

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27
Q

how do alkylating agents function?

A

covalently bind to/modify biological molecules
DNA is key target
must be reactive – inherent, or generated by metabolism

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28
Q

what is the mechanism of action for alkylating agents?

A

covalent modification of DNA
alters structure and complementarity of bases
most are bifunctional
blocks access to DNA by cross linking

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29
Q

mechanisms of resistance to alkylating agents

A

impermeable to drug, pump drug out
alternate targets for drug (Glutathione good at trapping reactive intermediates)
increased DNA repair
no apoptosis

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30
Q

what is an adverse effect of alkylating agents?

A

target rapidly growing cells (GM, GI, sperm)

  • see decreased leukocytes and platelets (dose limiting)
  • max suppression 10 days- 4 weeks after therapy
  • recovery 3-6 weeks after drug
  • monitor patient tolerance : CBC, hematocrit
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31
Q

why is there a risk of secondary malignancy with alkylating agents

A

anti cancer alkylating agents act in the same manner as carcinogens (covalent modification of nuclear DNA leading to altered structure and function)
concern is inversely proportional to age of patient

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32
Q

what are the alkylating agents discussed?

A 
mechlorethamine
cyclophosphamide
cis-platin
carboplatin
oxaliplatin
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33
Q

what is the mechanism of mechlorethamine

A

nitrogen mustard

first alkylating agent

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34
Q

mechlorethamine pharmacokinetics

A

IV only (subQ causes slough, necrosis)
make sure IV stays in vein to dilute drug
often in arterial supply to tumor
half life several minutes, reacts rapidly

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35
Q

primary use of mechlorethamine

A

Hodgkin’s disease, part of “MOPP”

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36
Q

cyclophosphamide pharmacokinetics

A

oral or IV

activated by host metabolism (in liver)

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37
Q

cyclophosphamide adverse effects (different from alkylating agents in general)

A

alopecia

sterile hemorrhagic cystitis

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38
Q

what is sterile hemorrhagic cystitis and how can it be prevented

A

acrolein, a toxic metabolite of cyclophosphamide, is a major cause of cystitis
protect from this by forced hydration
can co-administer Mesna (thiol which reacts with acrolein in urine to protect epithelium)

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39
Q

mechanism of cis-platin

A

bifunctional platinating agent which cross links DNA

blocks DNA synthesis

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40
Q

cis-platin pharmacokinetics

A

administer IV, cleared in urine

relatively non-toxic to bone marrow

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41
Q

acute adverse effects of cis-platin

A

severe nausea and vomiting (use HT3 antagonists)

renal toxicity is dose limiting, ensure adequate hydration

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42
Q

how does carboplatin differ from cis-platin

A

less nausea and renal, more myelosuppression

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43
Q

how does oxaliplatin differ from cis-platin

A

less renal, but neurotoxic

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44
Q

what is the general function of antimetabolites

A

analog of normal component of the target cell

enters into a normal metabolic pathway, but then blocks the pathway

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45
Q

what are the 3 classes of anticancer antimetabolites

A 
folate analogs (methotrexate)
purine analogs (6-MP, 6-TG)
pyrimidine analogs (5-FU, cytarabine, gemcitabine)
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46
Q

methotrexate mechanism

A

dihydrofolate reductase (DHFR) substrate inhibitor
tumor cells more sensitive than normal cells
greater accumulation in tumor cells
blocks production of bases for DNA synthesis

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47
Q

methotrexate pharmacokinetics

A

oral, IV, or intrathecally (CSF)
excreted in urine
may give high dose, followed by “rescue” with folinic acid
^^efficacy of this debated

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48
Q

methotrexate adverse effects

A

anti-folate effects (bone marrow, GI)

chronic use can produce hepatotoxicity

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49
Q

methotrexate resistance mechanisms

A

decreased drug accumulation
amplified DHFR
altered DHFR

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50
Q

what is the general mechanism of purine and pyrimidine analogs?

A

compete with normal bases, block/alter nucleic acid synthesis
all are activated by metabolism in pathways for nucleic acid synthesis

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51
Q

what are the purine analogs

A

6-mercaptopurine

6-thioguanine

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52
Q

purine analog pharmacokinetics

A

oral administration
well tolerated; BM suppression only at high doses
inactivated and cleared by TPMT (polymorphic, need genotype pre-treatment)

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53
Q

6-MP mechanism

A

inhibits AMP and GMP synthesis

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54
Q

6-TG mechanism

A

incorporates into RNA and DNA, altering function

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55
Q

general mechanism of purine analogs

A

just bases, no sugar attached
get converted to nucleosides with sugar through salvage pathway for activation
hprt enzyme responsible for this conversion
nucleoside products block DNA and RNA synthesis

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56
Q

resistance to purine analogs

A

decrease in hprt activity

increase in alkaline phosphatase

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57
Q

what are the pyrimidine analogs

A

5-FLuorouracil
Cytarabine
Gemcitabine

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58
Q

pyrimidine analog pharmacokinetics

A

generally more toxic than purines

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59
Q

5-FU mechanism

A

inhibits thymidylate synthase (thymineless death)

enhanced by folinic acid (ensure that there is a folic acid molecule as a cofactor in the rxn)

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60
Q

cytarabine mechanism

A

cytosine analog, chain terminator

61
Q

gemcitabine mechanism

A

cytosine analog, inhibits polymerase and chain terminator

62
Q

antitumor antibiotics mechanism

A

most produced by microbes (Streptomyces)
interact with DNA and/or RNA but most do not alkylate
block access to/function of DNA or RNA

63
Q

antitumor antibiotics pharmacokinetics

A

administered IV

unique toxicities associated with each

64
Q

what are the anthracyclines

A

doxorubicin

daunorubicin

65
Q

anthracyclines mechanism

A

intercalate into DNA
block topoisomerase II, inhibit DNA and RNA synthesis, cause strand breaks
generate free radicals which further clip DNA strands

66
Q

anthracycline pharmacokinetics

A

IV

metabolized in liver

67
Q

anthracycline adverse effects

A

BM suppression, GI distress, severe alopecia
SIGNATURE: cardiotoxicity
-function of cumulative dose
-arrhythmias, cardiomyopathy, CHF
-free radical mechanism (minimize with Dexrazoxane)

68
Q

how does Dexrazoxane work?

A

scavenges iron and free radicals to prevent cardiac toxicity of anthracyclines

69
Q

bleomycin mechanism

A

mixture of glycopeptides
binds DNA, generates radicals
-causes strand breaks
-active in G2 (CCS)

70
Q

bleomycin adverse effects

A

hypersensitivity, cutaneous reactions

pulmonary toxicity and fibrosis

71
Q

what are the two classes of microtubule poisons?

A

Vinca

Taxanes

72
Q

what are the vinca microtubule poisons?

A

vinblastine

vincristine

73
Q

what are the taxane microtubule poisons?

A

paclitaxel

docetaxel

74
Q

what is the mechanism of vinca microtubule poisons

A

inhibits/reverses tubulin polymerization
disrupts mitotic spindles
causes metaphase arrest

75
Q

vinca pharmacokinetics

A

IV

biliary excretion

76
Q

vinblastine adverse effects

A

nausea and vomiting
alopecia
bone marrow depression

77
Q

vincristine adverse effects

A

similar to vinblastine
less toxic to bone marrow
no nausea and vomiting
use limited to short duration due to peripheral neuropathy

78
Q

what is the mechanism of taxane microtubule poisons

A

affects microtubules by stabilization
blocks progress through mitosis
build spindles but can’t contract

79
Q

taxane pharmacokinetics

A

IV (in Cremophor, or nanoparticles to solubilize)

promising results in many solid tumors

80
Q

taxane adverse effects

A

acute hypersensitivity
nausea
delayed bone marrow suppression
some neuropathy

81
Q

what are the topoisomerase inhibitors

A

etoposide (VP-16)

irinotecan

82
Q

mechanism of etoposide

A

topoisomerase II inhibitor
causes double strand breaks by preventing ligation
DNA degradation
arrests cell in S-G2 stage

83
Q

etoposide pharmacokinetics

A

oral and IV

84
Q

etoposide adverse effects

A

nausea and vomiting
alopecia
bone marrow suppression

85
Q

irinotecan mechanism

A

pro-drug
converted to active SN-38 by esterase
SN-38 inhibits topoisomerase I

86
Q

irinotecan adverse effects

A

acute: nausea, vomiting, diarrhea
delayed: bone marrow suppression, nausea, dose limiting diarrhea

87
Q

irinotecan metabolism

A

active form, SN-38, inactivated by UGT1A1
UGT1A1 highly polymorphic, if there is low activity, a person can suffer from toxic drug effects at lower doses
deficient UGT1A1 activity can also contribute to hematological toxicity

88
Q

overall, what is the purpose of targeted therapies?

A

inhibit specific signaling pathways driving proliferation (not machinery itself)

  • inhibit agonist synthesis or release
  • agonist scavengers
  • receptor antagonist
  • anti-receptor MAb
  • kinase inhibitors
89
Q

describe the purpose of hormonal therapy

A

growth and differentiation of many tissues is under hormonal control
malignant cells derived from such a tissue may retain hormonal control
activity requires functional hormone receptor

90
Q

give examples of 3 hormones that may cause malignancies

A

androgens- prostate
estrogens- breast, uterus, cervix
corticosteroids- leukocytes, lymphocytes

91
Q

what are the adrenocorticosteroid drugs

A

hydrocortisone

prednisone

92
Q

mechanism of adrenocorticosteroids

A

suppress proliferation of immune cells

93
Q

adrenocorticosteroid pharmacokinetics

A

oral

used for leukemia and lymphomas

94
Q

adrenocorticosteroid adverse effects

A

delayed adverse effects include fluid retention, immunosuppression, and diabetes

95
Q

what are the aromatase inhibitors

A

anastrazole

letrozole

96
Q

mechanism of aromatase inhibitors

A

blocks conversion of androgens to estrogens

specific for estrogen production, depletes estrogen to modulate growth of estrogen driven tumors

97
Q

target of aromatase inhibitors

A

treatment for ER+ primary and metastatic breast cancer

98
Q

adverse effects of aromatase inhibitors

A

acute- mild nausea, headache

delayed- fatigue, hot flushes (drug induced menopause)

99
Q

what is a SERM

A

selective estrogen receptor antagonists

Tamoxifen

100
Q

Tamoxifen mechanism

A

ER antagonist in breast
ER agonist in endometrium (may increase risk of cancer w chronic use)
chemopreventive use against breast cancer

101
Q

target of Tamoxifen

A

treatment for ER+ primary and metastatic breast cancer

102
Q

Tamoxifen pharmacokinetics

A

oral

activated by CYP2D6

103
Q

Tamoxifen adverse effects

A

nausea, hot flushes, vaginal bleeding

104
Q

what drug is an androgen receptor antagonist?

A

flutamide

105
Q

flutamide mechanism

A

non-steroidal ligand for AR

diminished androgen effects

106
Q

flutamide pharmacokinetics

A

oral

used with radiation for prostate cancer

107
Q

flutamide adverse effects

A

nausea, hot flushes, transient hepatic effects

108
Q

what are the biological antineoplastic agents

A

inferferon a

trastuzumab (Herceptin)

109
Q

interferon a mechanism

A

polypeptide cytokine produced by white blood cells

alters gene expression, antiviral and immunomodulatory

110
Q

interferon a pharmacokinetics

A

parenteral admin

111
Q

targets of interferon a

A

hematologic malignancies, metastatic melanoma, renal cell carcinoma

112
Q

interferon a adverse effects

A

fever and chills, anorexia, weakness

113
Q

trastuzumab mechanism

A

monoclonal Ab against HER2neu/ErbB-2 oncogene product (epidermal growth factor receptor)
receptor is amplified in 25% of breast cancers, poor prognosis

114
Q

trastuzumab pharmacokinetics

A

IV

doesn’t cross blood brain barrier

115
Q

trastuzumab adverse effects

A

infusion reactions
hypersensitivity
cardiomyopathy

116
Q

targets of trastuzumab

A

HER2neu+ primary and metastatic breast tumors when pharmacokinetics allow

117
Q

what are the tyrosine kinase inhibitors

A

imatinib
dasatinib
gefitinib (iressa)

118
Q

imantinib mechanism

A

inhibits Bcr-Abl and other tyrosine kinases
blocks growth factor signaling in CML
blocks kit kinase in GI stromal tumors

119
Q

imantinib adverse effects

A

myelosuppressive
edema and fluid retention
hepatotoxicity

120
Q

dasatinib

A

2nd gen Bcr-Abl inhibitor

overcome some Imatinib resistance

121
Q

gefitinib mechanism

A

inhibits EGF-R tyrosine kinase

122
Q

gefitinib pharmacokinetics

A

oral

123
Q

targets of gefitinib

A

non small cell lung cancer
women, non smokes, Asians (most likely to have targeted mutation)
not very effective in gen pop, but effective in designated groups

124
Q

what is the purpose of signal transduction inhibitors

A

transform cancer from curable disease into a manageable disease (metabolically shut it down)

125
Q

Sirolimus mechanism

A

inhibits mTORC1, downstream component of PI3K signaling pathway
immunosuppressant, inhibits cell cycle progression and angiogenesis, promotes apoptosis

126
Q

Sirolimus pharmacokinetics

A

oral
60 hr half life
CYP3A substrate

127
Q

Sirolimus adverse effects

A

rash
mucositis
anemia
fatigue

128
Q

Bevacizumab mechanism

A

humanized Ab against VEGF-A
decreases vascularization
increases capillary permeability
first approved anti-angiogenic agent

129
Q

Bevacizumab pharmacokinetics

A

IV
4 wk half life
single agent for glioblastoma
combined with conventional chemo for several epithelial cancers

130
Q

Bevacizumab adverse effects

A

risk of blood vessel injury, bleeding
hypertension
proteinuria
arterial thromboembolic events

131
Q

Bortezomib mechanism

A

inhibits 26S proteasome

  • disrupts multiple intracellular signaling cascades
  • leads to apoptosis due to a damaged protein collection
132
Q

Bortezomib pharmacokinetics

A

IV
plasma half life 5.5 h
half life of inhibition 24 h
multiple myeloma, mantle cell lymphoma

133
Q

Bortezomib adverse effects

A

causes thrombocytopenia, fatigue, peripheral neuropathy

134
Q

what are the 2 targets of immune checkpoint inhibitors?

A

CTLA-4

PD-1/PD-1 Ligand

135
Q

what is the function of CTLA-4

A

upregulated during antigen priming of T cells

attenuated T cell response to reduce risk of autoimmune inflammation

136
Q

what is the function of PD-1/PD-L1

A

activation of PD-1 inhibits immune response, inactivated T cells
PD-L1 expression on tumor cells protects them from T cell attack

137
Q

mechanism of Ipilimumab

A

human Mab against CTLA-4

blocks interaction with B7 enhancing T-cell activation

138
Q

Ipilimumab pharmacokinetics

A

IV

usually q21 days x 4

139
Q

targets of Ipilimumab

A

unresectable of metastatic melanoma

140
Q

Ipilimumab adverse effects

A

immune-inflammatory adverse effects

skin, GI most common sites followed by liver, pituitary, and thyroid

141
Q

Nivolumab mechanism

A

human Mab against PD-1

blocks interaction with PD-1 ligands, restore of maintain T cell antitumor response

142
Q

Nivolumab pharmacokinetics

A

IV
q14 days
better tolerated than CTLA-4 inhibitors

143
Q

targets of Nivolumab

A

advanced/previously treated melanoma, NSCLC, RCC, head and neck, Hodgkin

144
Q

Nivolumab adverse effects

A

rash for melanoma pts
fatigue, dyspnea for NSCLC
treat adverse effects with corticosteroids

145
Q

Atezolimumab mechanism

A

human Mab against PD-L1

blocks interaction with PD-1, promote T cell antitumor response

146
Q

Atezolimumab pharmacokinetics

A

IV
q21 days
better tolerated than CTLA-4 inhibitors

147
Q

targets of Atezolimumab

A

treatment resistant metastatic NSCLC

advanced or metastatic urothelial cancer

148
Q

Atezolimumab adverse effects

A

fatigue, dyspnea, cough, nausea for NSCLC
UTI for urothelial cancer pts
occasional immune mediated effects (liver, GI, endocrine)

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