B3.042,B3.079 Anticancer Chemotherapy Flashcards
describe selective toxicity
targeting a pathogen rather than the host
goal of chemotherapy
relative, not usually absolute
how is selective toxicity generally achieved in cancer treatment?
target is more essential in pathogen than in host
- greater utilization in tumor than in host
- the least selective path
what are the 5 general characteristics of tumor cells
excessive/inappropriate growth diminished apoptosis loss of differentiation invasive metastatic
why is early detection of cancer key?
symptoms appear very close in the timeline of pathogenesis to death
what is the main goal of chemo?
to kill all tumor cells with the potential for proliferation
what are determinants of success in cancer treatment
efficacy, frequency, and duration
adjuvant
chemotherapy following surgery or radiation
neoadjuvant
chemotherapy before surgery or radiation
what % of cancers can be cured using multi-modality therapy?
50%
what % of cancers can be cured with chemo alone?
17%
describe the relationship between the cell cycle and chemotherapy
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
why might drugs be less effective on a cell in the G0 phase?
drugs induce damage on DNA
race between repair and replication
if in G0, the cell has more time to repair the damage
why is targeting tumor cells’ high proliferative potential a problem?
normal cell populations can also have this high proliferative potential
-key factor in adverse effects
what are normal cell populations that have high proliferative potentials
BM
epithelial cells
immune system
hair follicles
what do most effective anticancer drugs activate?
apoptosis
does not occur in the absence of functional p53
what are some generalized acute effects of chemo?
nausea and vomiting
can cause dehydration, malnutrition, and metabolic disorders
how can acute effects of chemo be treated?
antimetics
-5-HT3 antagonists (Odansetron)
-Phenothiazines (sedatives)
30% unaffected by antimetics
what are some delayed effects of chemo on bone marrow?
myelosuppression
- usually leukopenia (neutropenia) and thrombocytopenia
- risk of bleeding, infection
- pancytopenia
how can delayed effects of chemo on bone marrow be treated?
GM-CSF (granulocyte macrophage colony stimulating factor)
platelet transfusions
EPO (erythropoietin)
what are some other delayed effects of chemo?
GI effects -diarrhea, mucositis, stomatitis prolonged myelosuppression alopecia neuropathies hand and foot syndrome (neuropathy + hemodynamic changes) "signature" adverse effects
what is primary resistance
tumor cells initially not sensitive to a given drug (test by in vitro sensitivity or tumor genotype)
what is secondary resistance
tumor cells develop resistance during therapy
amplification/alteration of targets
enhanced repair
changes in permeability
what is P-glycoprotein?
Pgp, MDR-1
efflux pump that can export multiple calluses of anti-cancer drugs
-antimetabolites, antibiotics, alkaloids, et al.
what are the major classes of antineoplastic drugs
alkylating agents antimetabolites antitumor antibiotics microtubule poisons topoisomerase inhibitors targeted therapies* (not cytotoxic)
what are the 4 main classes of targeted therapies
hormones/hormone modulators
biologicals
tyrosine kinase inhibitors
other
what is the generalized benefit of targeted therapies
more selective for targeting tumor
fewer adverse effects
how do alkylating agents function?
covalently bind to/modify biological molecules
DNA is key target
must be reactive – inherent, or generated by metabolism
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
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
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
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
what are the alkylating agents discussed?
mechlorethamine cyclophosphamide cis-platin carboplatin oxaliplatin
what is the mechanism of mechlorethamine
nitrogen mustard
first alkylating agent
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
primary use of mechlorethamine
Hodgkin’s disease, part of “MOPP”
cyclophosphamide pharmacokinetics
oral or IV
activated by host metabolism (in liver)
cyclophosphamide adverse effects (different from alkylating agents in general)
alopecia
sterile hemorrhagic cystitis
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)
mechanism of cis-platin
bifunctional platinating agent which cross links DNA
blocks DNA synthesis
cis-platin pharmacokinetics
administer IV, cleared in urine
relatively non-toxic to bone marrow
acute adverse effects of cis-platin
severe nausea and vomiting (use HT3 antagonists)
renal toxicity is dose limiting, ensure adequate hydration
how does carboplatin differ from cis-platin
less nausea and renal, more myelosuppression
how does oxaliplatin differ from cis-platin
less renal, but neurotoxic
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
what are the 3 classes of anticancer antimetabolites
folate analogs (methotrexate) purine analogs (6-MP, 6-TG) pyrimidine analogs (5-FU, cytarabine, gemcitabine)
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
methotrexate pharmacokinetics
oral, IV, or intrathecally (CSF)
excreted in urine
may give high dose, followed by “rescue” with folinic acid
^^efficacy of this debated
methotrexate adverse effects
anti-folate effects (bone marrow, GI)
chronic use can produce hepatotoxicity
methotrexate resistance mechanisms
decreased drug accumulation
amplified DHFR
altered DHFR
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
what are the purine analogs
6-mercaptopurine
6-thioguanine
purine analog pharmacokinetics
oral administration
well tolerated; BM suppression only at high doses
inactivated and cleared by TPMT (polymorphic, need genotype pre-treatment)
6-MP mechanism
inhibits AMP and GMP synthesis
6-TG mechanism
incorporates into RNA and DNA, altering function
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
resistance to purine analogs
decrease in hprt activity
increase in alkaline phosphatase
what are the pyrimidine analogs
5-FLuorouracil
Cytarabine
Gemcitabine
pyrimidine analog pharmacokinetics
generally more toxic than purines
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)
cytarabine mechanism
cytosine analog, chain terminator
gemcitabine mechanism
cytosine analog, inhibits polymerase and chain terminator
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
antitumor antibiotics pharmacokinetics
administered IV
unique toxicities associated with each
what are the anthracyclines
doxorubicin
daunorubicin
anthracyclines mechanism
intercalate into DNA
block topoisomerase II, inhibit DNA and RNA synthesis, cause strand breaks
generate free radicals which further clip DNA strands
anthracycline pharmacokinetics
IV
metabolized in liver
anthracycline adverse effects
BM suppression, GI distress, severe alopecia
SIGNATURE: cardiotoxicity
-function of cumulative dose
-arrhythmias, cardiomyopathy, CHF
-free radical mechanism (minimize with Dexrazoxane)
how does Dexrazoxane work?
scavenges iron and free radicals to prevent cardiac toxicity of anthracyclines
bleomycin mechanism
mixture of glycopeptides
binds DNA, generates radicals
-causes strand breaks
-active in G2 (CCS)
bleomycin adverse effects
hypersensitivity, cutaneous reactions
pulmonary toxicity and fibrosis
what are the two classes of microtubule poisons?
Vinca
Taxanes
what are the vinca microtubule poisons?
vinblastine
vincristine
what are the taxane microtubule poisons?
paclitaxel
docetaxel
what is the mechanism of vinca microtubule poisons
inhibits/reverses tubulin polymerization
disrupts mitotic spindles
causes metaphase arrest
vinca pharmacokinetics
IV
biliary excretion
vinblastine adverse effects
nausea and vomiting
alopecia
bone marrow depression
vincristine adverse effects
similar to vinblastine
less toxic to bone marrow
no nausea and vomiting
use limited to short duration due to peripheral neuropathy
what is the mechanism of taxane microtubule poisons
affects microtubules by stabilization
blocks progress through mitosis
build spindles but can’t contract
taxane pharmacokinetics
IV (in Cremophor, or nanoparticles to solubilize)
promising results in many solid tumors
taxane adverse effects
acute hypersensitivity
nausea
delayed bone marrow suppression
some neuropathy
what are the topoisomerase inhibitors
etoposide (VP-16)
irinotecan
mechanism of etoposide
topoisomerase II inhibitor
causes double strand breaks by preventing ligation
DNA degradation
arrests cell in S-G2 stage
etoposide pharmacokinetics
oral and IV
etoposide adverse effects
nausea and vomiting
alopecia
bone marrow suppression
irinotecan mechanism
pro-drug
converted to active SN-38 by esterase
SN-38 inhibits topoisomerase I
irinotecan adverse effects
acute: nausea, vomiting, diarrhea
delayed: bone marrow suppression, nausea, dose limiting diarrhea
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
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
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
give examples of 3 hormones that may cause malignancies
androgens- prostate
estrogens- breast, uterus, cervix
corticosteroids- leukocytes, lymphocytes
what are the adrenocorticosteroid drugs
hydrocortisone
prednisone
mechanism of adrenocorticosteroids
suppress proliferation of immune cells
adrenocorticosteroid pharmacokinetics
oral
used for leukemia and lymphomas
adrenocorticosteroid adverse effects
delayed adverse effects include fluid retention, immunosuppression, and diabetes
what are the aromatase inhibitors
anastrazole
letrozole
mechanism of aromatase inhibitors
blocks conversion of androgens to estrogens
specific for estrogen production, depletes estrogen to modulate growth of estrogen driven tumors
target of aromatase inhibitors
treatment for ER+ primary and metastatic breast cancer
adverse effects of aromatase inhibitors
acute- mild nausea, headache
delayed- fatigue, hot flushes (drug induced menopause)
what is a SERM
selective estrogen receptor antagonists
Tamoxifen
Tamoxifen mechanism
ER antagonist in breast
ER agonist in endometrium (may increase risk of cancer w chronic use)
chemopreventive use against breast cancer
target of Tamoxifen
treatment for ER+ primary and metastatic breast cancer
Tamoxifen pharmacokinetics
oral
activated by CYP2D6
Tamoxifen adverse effects
nausea, hot flushes, vaginal bleeding
what drug is an androgen receptor antagonist?
flutamide
flutamide mechanism
non-steroidal ligand for AR
diminished androgen effects
flutamide pharmacokinetics
oral
used with radiation for prostate cancer
flutamide adverse effects
nausea, hot flushes, transient hepatic effects
what are the biological antineoplastic agents
inferferon a
trastuzumab (Herceptin)
interferon a mechanism
polypeptide cytokine produced by white blood cells
alters gene expression, antiviral and immunomodulatory
interferon a pharmacokinetics
parenteral admin
targets of interferon a
hematologic malignancies, metastatic melanoma, renal cell carcinoma
interferon a adverse effects
fever and chills, anorexia, weakness
trastuzumab mechanism
monoclonal Ab against HER2neu/ErbB-2 oncogene product (epidermal growth factor receptor)
receptor is amplified in 25% of breast cancers, poor prognosis
trastuzumab pharmacokinetics
IV
doesn’t cross blood brain barrier
trastuzumab adverse effects
infusion reactions
hypersensitivity
cardiomyopathy
targets of trastuzumab
HER2neu+ primary and metastatic breast tumors when pharmacokinetics allow
what are the tyrosine kinase inhibitors
imatinib
dasatinib
gefitinib (iressa)
imantinib mechanism
inhibits Bcr-Abl and other tyrosine kinases
blocks growth factor signaling in CML
blocks kit kinase in GI stromal tumors
imantinib adverse effects
myelosuppressive
edema and fluid retention
hepatotoxicity
dasatinib
2nd gen Bcr-Abl inhibitor
overcome some Imatinib resistance
gefitinib mechanism
inhibits EGF-R tyrosine kinase
gefitinib pharmacokinetics
oral
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
what is the purpose of signal transduction inhibitors
transform cancer from curable disease into a manageable disease (metabolically shut it down)
Sirolimus mechanism
inhibits mTORC1, downstream component of PI3K signaling pathway
immunosuppressant, inhibits cell cycle progression and angiogenesis, promotes apoptosis
Sirolimus pharmacokinetics
oral
60 hr half life
CYP3A substrate
Sirolimus adverse effects
rash
mucositis
anemia
fatigue
Bevacizumab mechanism
humanized Ab against VEGF-A
decreases vascularization
increases capillary permeability
first approved anti-angiogenic agent
Bevacizumab pharmacokinetics
IV
4 wk half life
single agent for glioblastoma
combined with conventional chemo for several epithelial cancers
Bevacizumab adverse effects
risk of blood vessel injury, bleeding
hypertension
proteinuria
arterial thromboembolic events
Bortezomib mechanism
inhibits 26S proteasome
- disrupts multiple intracellular signaling cascades
- leads to apoptosis due to a damaged protein collection
Bortezomib pharmacokinetics
IV
plasma half life 5.5 h
half life of inhibition 24 h
multiple myeloma, mantle cell lymphoma
Bortezomib adverse effects
causes thrombocytopenia, fatigue, peripheral neuropathy
what are the 2 targets of immune checkpoint inhibitors?
CTLA-4
PD-1/PD-1 Ligand
what is the function of CTLA-4
upregulated during antigen priming of T cells
attenuated T cell response to reduce risk of autoimmune inflammation
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
mechanism of Ipilimumab
human Mab against CTLA-4
blocks interaction with B7 enhancing T-cell activation
Ipilimumab pharmacokinetics
IV
usually q21 days x 4
targets of Ipilimumab
unresectable of metastatic melanoma
Ipilimumab adverse effects
immune-inflammatory adverse effects
skin, GI most common sites followed by liver, pituitary, and thyroid
Nivolumab mechanism
human Mab against PD-1
blocks interaction with PD-1 ligands, restore of maintain T cell antitumor response
Nivolumab pharmacokinetics
IV
q14 days
better tolerated than CTLA-4 inhibitors
targets of Nivolumab
advanced/previously treated melanoma, NSCLC, RCC, head and neck, Hodgkin
Nivolumab adverse effects
rash for melanoma pts
fatigue, dyspnea for NSCLC
treat adverse effects with corticosteroids
Atezolimumab mechanism
human Mab against PD-L1
blocks interaction with PD-1, promote T cell antitumor response
Atezolimumab pharmacokinetics
IV
q21 days
better tolerated than CTLA-4 inhibitors
targets of Atezolimumab
treatment resistant metastatic NSCLC
advanced or metastatic urothelial cancer
Atezolimumab adverse effects
fatigue, dyspnea, cough, nausea for NSCLC
UTI for urothelial cancer pts
occasional immune mediated effects (liver, GI, endocrine)
