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
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
3
Q
what are the 5 general characteristics of tumor cells
A
excessive/inappropriate growth diminished apoptosis loss of differentiation invasive metastatic
4
Q
why is early detection of cancer key?
A
symptoms appear very close in the timeline of pathogenesis to death
5
Q
what is the main goal of chemo?
A
to kill all tumor cells with the potential for proliferation
6
Q
what are determinants of success in cancer treatment
A
efficacy, frequency, and duration
7
Q
adjuvant
A
chemotherapy following surgery or radiation
8
Q
neoadjuvant
A
chemotherapy before surgery or radiation
9
Q
what % of cancers can be cured using multi-modality therapy?
A
50%
10
Q
what % of cancers can be cured with chemo alone?
A
17%
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
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
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
14
Q
what are normal cell populations that have high proliferative potentials
A
BM
epithelial cells
immune system
hair follicles
15
Q
what do most effective anticancer drugs activate?
A
apoptosis
does not occur in the absence of functional p53
16
Q
what are some generalized acute effects of chemo?
A
nausea and vomiting
can cause dehydration, malnutrition, and metabolic disorders
17
Q
how can acute effects of chemo be treated?
A
antimetics
-5-HT3 antagonists (Odansetron)
-Phenothiazines (sedatives)
30% unaffected by antimetics
18
Q
what are some delayed effects of chemo on bone marrow?
A
myelosuppression
- usually leukopenia (neutropenia) and thrombocytopenia
- risk of bleeding, infection
- pancytopenia
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)
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
21
Q
what is primary resistance
A
tumor cells initially not sensitive to a given drug (test by in vitro sensitivity or tumor genotype)
22
Q
what is secondary resistance
A
tumor cells develop resistance during therapy
amplification/alteration of targets
enhanced repair
changes in permeability
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.
24
Q
what are the major classes of antineoplastic drugs
A
alkylating agents antimetabolites antitumor antibiotics microtubule poisons topoisomerase inhibitors targeted therapies* (not cytotoxic)
25
what are the 4 main classes of targeted therapies
hormones/hormone modulators
biologicals
tyrosine kinase inhibitors
other
26
what is the generalized benefit of targeted therapies
more selective for targeting tumor
| fewer adverse effects
27
how do alkylating agents function?
covalently bind to/modify biological molecules
DNA is key target
must be reactive -- inherent, or generated by metabolism
28
what is the mechanism of action for alkylating agents?
covalent modification of DNA
alters structure and complementarity of bases
most are bifunctional
blocks access to DNA by cross linking
29
mechanisms of resistance to alkylating agents
impermeable to drug, pump drug out
alternate targets for drug (Glutathione good at trapping reactive intermediates)
increased DNA repair
no apoptosis
30
what is an adverse effect of alkylating agents?
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
31
why is there a risk of secondary malignancy with alkylating agents
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
32
what are the alkylating agents discussed?
```
mechlorethamine
cyclophosphamide
cis-platin
carboplatin
oxaliplatin
```
33
what is the mechanism of mechlorethamine
nitrogen mustard
| first alkylating agent
34
mechlorethamine pharmacokinetics
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
35
primary use of mechlorethamine
Hodgkin's disease, part of "MOPP"
36
cyclophosphamide pharmacokinetics
oral or IV
| activated by host metabolism (in liver)
37
cyclophosphamide adverse effects (different from alkylating agents in general)
alopecia
| sterile hemorrhagic cystitis
38
what is sterile hemorrhagic cystitis and how can it be prevented
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)
39
mechanism of cis-platin
bifunctional platinating agent which cross links DNA
| blocks DNA synthesis
40
cis-platin pharmacokinetics
administer IV, cleared in urine
| relatively non-toxic to bone marrow
41
acute adverse effects of cis-platin
severe nausea and vomiting (use HT3 antagonists)
| renal toxicity is dose limiting, ensure adequate hydration
42
how does carboplatin differ from cis-platin
less nausea and renal, more myelosuppression
43
how does oxaliplatin differ from cis-platin
less renal, but neurotoxic
44
what is the general function of antimetabolites
analog of normal component of the target cell
| enters into a normal metabolic pathway, but then blocks the pathway
45
what are the 3 classes of anticancer antimetabolites
```
folate analogs (methotrexate)
purine analogs (6-MP, 6-TG)
pyrimidine analogs (5-FU, cytarabine, gemcitabine)
```
46
methotrexate mechanism
dihydrofolate reductase (DHFR) substrate inhibitor
tumor cells more sensitive than normal cells
greater accumulation in tumor cells
blocks production of bases for DNA synthesis
47
methotrexate pharmacokinetics
oral, IV, or intrathecally (CSF)
excreted in urine
may give high dose, followed by "rescue" with folinic acid
^^efficacy of this debated
48
methotrexate adverse effects
anti-folate effects (bone marrow, GI)
| chronic use can produce hepatotoxicity
49
methotrexate resistance mechanisms
decreased drug accumulation
amplified DHFR
altered DHFR
50
what is the general mechanism of purine and pyrimidine analogs?
compete with normal bases, block/alter nucleic acid synthesis
all are activated by metabolism in pathways for nucleic acid synthesis
51
what are the purine analogs
6-mercaptopurine
| 6-thioguanine
52
purine analog pharmacokinetics
oral administration
well tolerated; BM suppression only at high doses
inactivated and cleared by TPMT (polymorphic, need genotype pre-treatment)
53
6-MP mechanism
inhibits AMP and GMP synthesis
54
6-TG mechanism
incorporates into RNA and DNA, altering function
55
general mechanism of purine analogs
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
56
resistance to purine analogs
decrease in hprt activity
| increase in alkaline phosphatase
57
what are the pyrimidine analogs
5-FLuorouracil
Cytarabine
Gemcitabine
58
pyrimidine analog pharmacokinetics
generally more toxic than purines
59
5-FU mechanism
inhibits thymidylate synthase (thymineless death)
| enhanced by folinic acid (ensure that there is a folic acid molecule as a cofactor in the rxn)
60
cytarabine mechanism
cytosine analog, chain terminator
61
gemcitabine mechanism
cytosine analog, inhibits polymerase and chain terminator
62
antitumor antibiotics mechanism
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
antitumor antibiotics pharmacokinetics
administered IV
| unique toxicities associated with each
64
what are the anthracyclines
doxorubicin
| daunorubicin
65
anthracyclines mechanism
intercalate into DNA
block topoisomerase II, inhibit DNA and RNA synthesis, cause strand breaks
generate free radicals which further clip DNA strands
66
anthracycline pharmacokinetics
IV
| metabolized in liver
67
anthracycline adverse effects
BM suppression, GI distress, severe alopecia
SIGNATURE: cardiotoxicity
-function of cumulative dose
-arrhythmias, cardiomyopathy, CHF
-free radical mechanism (minimize with Dexrazoxane)
68
how does Dexrazoxane work?
scavenges iron and free radicals to prevent cardiac toxicity of anthracyclines
69
bleomycin mechanism
mixture of glycopeptides
binds DNA, generates radicals
-causes strand breaks
-active in G2 (CCS)
70
bleomycin adverse effects
hypersensitivity, cutaneous reactions
| pulmonary toxicity and fibrosis
71
what are the two classes of microtubule poisons?
Vinca
| Taxanes
72
what are the vinca microtubule poisons?
vinblastine
| vincristine
73
what are the taxane microtubule poisons?
paclitaxel
| docetaxel
74
what is the mechanism of vinca microtubule poisons
inhibits/reverses tubulin polymerization
disrupts mitotic spindles
causes metaphase arrest
75
vinca pharmacokinetics
IV
| biliary excretion
76
vinblastine adverse effects
nausea and vomiting
alopecia
bone marrow depression
77
vincristine adverse effects
similar to vinblastine
less toxic to bone marrow
no nausea and vomiting
use limited to short duration due to peripheral neuropathy
78
what is the mechanism of taxane microtubule poisons
affects microtubules by stabilization
blocks progress through mitosis
build spindles but can't contract
79
taxane pharmacokinetics
IV (in Cremophor, or nanoparticles to solubilize)
| promising results in many solid tumors
80
taxane adverse effects
acute hypersensitivity
nausea
delayed bone marrow suppression
some neuropathy
81
what are the topoisomerase inhibitors
etoposide (VP-16)
| irinotecan
82
mechanism of etoposide
topoisomerase II inhibitor
causes double strand breaks by preventing ligation
DNA degradation
arrests cell in S-G2 stage
83
etoposide pharmacokinetics
oral and IV
84
etoposide adverse effects
nausea and vomiting
alopecia
bone marrow suppression
85
irinotecan mechanism
pro-drug
converted to active SN-38 by esterase
SN-38 inhibits topoisomerase I
86
irinotecan adverse effects
acute: nausea, vomiting, diarrhea
delayed: bone marrow suppression, nausea, dose limiting diarrhea
87
irinotecan metabolism
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
overall, what is the purpose of targeted therapies?
inhibit specific signaling pathways driving proliferation (not machinery itself)
- inhibit agonist synthesis or release
- agonist scavengers
- receptor antagonist
- anti-receptor MAb
- kinase inhibitors
89
describe the purpose of hormonal therapy
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
give examples of 3 hormones that may cause malignancies
androgens- prostate
estrogens- breast, uterus, cervix
corticosteroids- leukocytes, lymphocytes
91
what are the adrenocorticosteroid drugs
hydrocortisone
| prednisone
92
mechanism of adrenocorticosteroids
suppress proliferation of immune cells
93
adrenocorticosteroid pharmacokinetics
oral
| used for leukemia and lymphomas
94
adrenocorticosteroid adverse effects
delayed adverse effects include fluid retention, immunosuppression, and diabetes
95
what are the aromatase inhibitors
anastrazole
| letrozole
96
mechanism of aromatase inhibitors
blocks conversion of androgens to estrogens
| specific for estrogen production, depletes estrogen to modulate growth of estrogen driven tumors
97
target of aromatase inhibitors
treatment for ER+ primary and metastatic breast cancer
98
adverse effects of aromatase inhibitors
acute- mild nausea, headache
| delayed- fatigue, hot flushes (drug induced menopause)
99
what is a SERM
selective estrogen receptor antagonists
| Tamoxifen
100
Tamoxifen mechanism
ER antagonist in breast
ER agonist in endometrium (may increase risk of cancer w chronic use)
chemopreventive use against breast cancer
101
target of Tamoxifen
treatment for ER+ primary and metastatic breast cancer
102
Tamoxifen pharmacokinetics
oral
| activated by CYP2D6
103
Tamoxifen adverse effects
nausea, hot flushes, vaginal bleeding
104
what drug is an androgen receptor antagonist?
flutamide
105
flutamide mechanism
non-steroidal ligand for AR
| diminished androgen effects
106
flutamide pharmacokinetics
oral
| used with radiation for prostate cancer
107
flutamide adverse effects
nausea, hot flushes, transient hepatic effects
108
what are the biological antineoplastic agents
inferferon a
| trastuzumab (Herceptin)
109
interferon a mechanism
polypeptide cytokine produced by white blood cells
| alters gene expression, antiviral and immunomodulatory
110
interferon a pharmacokinetics
parenteral admin
111
targets of interferon a
hematologic malignancies, metastatic melanoma, renal cell carcinoma
112
interferon a adverse effects
fever and chills, anorexia, weakness
113
trastuzumab mechanism
monoclonal Ab against HER2neu/ErbB-2 oncogene product (epidermal growth factor receptor)
receptor is amplified in 25% of breast cancers, poor prognosis
114
trastuzumab pharmacokinetics
IV
| doesn't cross blood brain barrier
115
trastuzumab adverse effects
infusion reactions
hypersensitivity
cardiomyopathy
116
targets of trastuzumab
HER2neu+ primary and metastatic breast tumors when pharmacokinetics allow
117
what are the tyrosine kinase inhibitors
imatinib
dasatinib
gefitinib (iressa)
118
imantinib mechanism
inhibits Bcr-Abl and other tyrosine kinases
blocks growth factor signaling in CML
blocks kit kinase in GI stromal tumors
119
imantinib adverse effects
myelosuppressive
edema and fluid retention
hepatotoxicity
120
dasatinib
2nd gen Bcr-Abl inhibitor
| overcome some Imatinib resistance
121
gefitinib mechanism
inhibits EGF-R tyrosine kinase
122
gefitinib pharmacokinetics
oral
123
targets of gefitinib
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
what is the purpose of signal transduction inhibitors
transform cancer from curable disease into a manageable disease (metabolically shut it down)
125
Sirolimus mechanism
inhibits mTORC1, downstream component of PI3K signaling pathway
immunosuppressant, inhibits cell cycle progression and angiogenesis, promotes apoptosis
126
Sirolimus pharmacokinetics
oral
60 hr half life
CYP3A substrate
127
Sirolimus adverse effects
rash
mucositis
anemia
fatigue
128
Bevacizumab mechanism
humanized Ab against VEGF-A
decreases vascularization
increases capillary permeability
first approved anti-angiogenic agent
129
Bevacizumab pharmacokinetics
IV
4 wk half life
single agent for glioblastoma
combined with conventional chemo for several epithelial cancers
130
Bevacizumab adverse effects
risk of blood vessel injury, bleeding
hypertension
proteinuria
arterial thromboembolic events
131
Bortezomib mechanism
inhibits 26S proteasome
- disrupts multiple intracellular signaling cascades
- leads to apoptosis due to a damaged protein collection
132
Bortezomib pharmacokinetics
IV
plasma half life 5.5 h
half life of inhibition 24 h
multiple myeloma, mantle cell lymphoma
133
Bortezomib adverse effects
causes thrombocytopenia, fatigue, peripheral neuropathy
134
what are the 2 targets of immune checkpoint inhibitors?
CTLA-4
| PD-1/PD-1 Ligand
135
what is the function of CTLA-4
upregulated during antigen priming of T cells
| attenuated T cell response to reduce risk of autoimmune inflammation
136
what is the function of PD-1/PD-L1
activation of PD-1 inhibits immune response, inactivated T cells
PD-L1 expression on tumor cells protects them from T cell attack
137
mechanism of Ipilimumab
human Mab against CTLA-4
| blocks interaction with B7 enhancing T-cell activation
138
Ipilimumab pharmacokinetics
IV
| usually q21 days x 4
139
targets of Ipilimumab
unresectable of metastatic melanoma
140
Ipilimumab adverse effects
immune-inflammatory adverse effects
| skin, GI most common sites followed by liver, pituitary, and thyroid
141
Nivolumab mechanism
human Mab against PD-1
| blocks interaction with PD-1 ligands, restore of maintain T cell antitumor response
142
Nivolumab pharmacokinetics
IV
q14 days
better tolerated than CTLA-4 inhibitors
143
targets of Nivolumab
advanced/previously treated melanoma, NSCLC, RCC, head and neck, Hodgkin
144
Nivolumab adverse effects
rash for melanoma pts
fatigue, dyspnea for NSCLC
treat adverse effects with corticosteroids
145
Atezolimumab mechanism
human Mab against PD-L1
| blocks interaction with PD-1, promote T cell antitumor response
146
Atezolimumab pharmacokinetics
IV
q21 days
better tolerated than CTLA-4 inhibitors
147
targets of Atezolimumab
treatment resistant metastatic NSCLC
| advanced or metastatic urothelial cancer
148
Atezolimumab adverse effects
fatigue, dyspnea, cough, nausea for NSCLC
UTI for urothelial cancer pts
occasional immune mediated effects (liver, GI, endocrine)
