Cancer Chemotherapy Flashcards
what categories of drugs make up the classical chemotherapeutic agents?
DNA damaging agents
Antimetabolites
Inhibitors of mitosis
DNA cross-linking drugs include:
Nitrogen mustards - cycolphosphamdie
[ - mechlorethamine, ifsofamide, chloroambucil, melphalan]
platinum analogs - cisplatin
DNA cleaving agents include:
bleomycin
Doxorubicin
Antimetabolites include which categories of drugs?
folic acid analogs
pyrimidine analogs
purine analogs
folic acid analogs include:
methrotrexate
leucovorin
pyrimidine analogs include
5-fluorouracil
purine analogs include
mercaptopurine
inhibitors of mitosis include:
pacitaxel (taxol)
cross linking agents work by:
covalently binding to DNA bases causing cross-linking of DNA strands
- usually at N7 guanine
prevents DNA replication and RNA synthesis
cyclophosphamide is what kind of drug?
DNA cross linking agent (nitrogen mustard)
cisplatin is what kind of drug?
DNA cross linking agent (platinum analog)
cyclophosphamide - activation and toxicity
P450
bone marrow suppression
cisplatin - toxicity
renal toxicity
DNA cleaving agents work by:
cleaving DNA which stalls/disrupts replication and transcription
bleomycin is what kind of drug?
DNA cleaving agent
bleomycin - activation and toxicity
activated by microsomal reduction
pulmonary toxicity
doxorubicin is what kind of drug?
DNA cleaving agent
doxorubicin - action, activation, and toxicity
freezes topoisomerase II in strand cleavage and rejoining cycles –> DNA breaks
achieved with oxygen free radicals
activated by flavin centered reductase
bone marrow suppression and cardiac toxicity
antimetabolites work by:
enzyme inhibitors and nucleotide analog - interfere with metabolic pathways
competitive inhibition or incorporation into DNA, RNA that causes premature chain termination and an abnormal product
what is the theory behind folic analog therapy?
tumor cells rapidly divide which requires a large amount of folic acid to generate nucleotides and AAs
methotrexate is what kind of drug?
folic acid analog
what is the mechanism of methotrexate?
- competitive inhibitor of dihydrofolate reductase (DHFR) which catalyzes FH2–>FH4
can’t make thymine nucleotides from uracil –> pyrimidine shortage - inhibits enzymes required for de novo purine synthesis
- impairs protein synthesis because it interferes with glycine and methionine synthesis
what is the major toxicity of methotrexate
bone marrow suppression
leukopenia and thrombocytopenia
leucovorin is what kind of drug?
folic acid analog (reduced)
what is the mechanism of leucovorin and why is it given?
used in the synthesis of purines and production of dTMP
functions to rescue normal cells by allowing them to partially recover after treatment with methotrexate
what is the theory behind pyrimidine and purine analogs as therapy?
become incorporated into nucleotides which results in DNA termination or an incorrect strand of DNA or RNA
fluorouracil is what kind of drug?
pyrimidine analog (uracil analog)
what is the mechanism of 5FU
uracil derivative is incorporated into RNA which prevents processing of rRNA into final product ==> 28 S ribosome
incorporation into DNA causes strand breaks
metabolite of 5FU (FdUMP) inhibits thymidylate synthase which prevents conversion of dUMP to dTMP
major toxicity of 5FU:
bone marrow suppression, oral and GI mucositis
mercaptopurine is what kind of drug
purine analog
what is the mechanism of mercaptopurine?
causes feedback inhibition of the first step in purine biosynthesis
results in decreased levels of purines available for nucleotide synthesis
also become incorproated in DNA causing strand breaks and inhibition of RNA synthesis
what is the major toxicity of mercaptopurine?
bone marrow suppression
Pacitaxel is what kind of drug?
mitosis inhibitor
what is the mechanism of pacitaxel
stabilizes microtubule formation causing arrest in G2 or mitosis
what is the major toxicity of pacitaxel?
neutropenia
what combination of drugs are frequently used to treat cervical cancer
cisplatin
bleomycin
methotrexate
what is the mechanism of selective estrogen receptor modulators (SERMs)
binds estrogen receptor (ER) on tumor cells that either mimics the effect of estrogen or has antiestrogenic effects
what are the three classes of drugs used to treat ER+ breast cancer?
SERMs aromatase inhibitors (AIs) Selective estrogen receptor downregulators (SERDs)
SERMs include:
tamoxifen
raloxifen
AIs include:
letrozole (femara)
SERDs include:
fulvestrant
what is the mechanism of tamoxifen
antiestrogenic effect - stops growth of tumor
in bone however, it mimics the effect of estrogen and promotes increased bone density
what is the effect of tamoxifen on post menopausal women
promotes cell growth of uterus and is associated with increased incidence of endometrial cancer (2/1000)
how can a tumor become resistant to tamoxifen
a mutation in P450 can prevent activation of tamoxifen
what is the mechanism of raloxifen
estrogenic effect on bone, antiestrogenic effects on uterine and breast
not effective against lobular carcinoma in situ and ductal carcinoma in situ
what is the mechanism of AIs
lower estrogen levels by inhibiting the aromatase that converts androstenedion to estrogen and estridiol
when is letrozole used?
adjuvent therapy in post menopausal patients following surgery to remove tomor
also used to treat advanced metastatic breast cancer in post menopausal patients
not associated with increased blood clot formation or endometrial cancer
when is letrozole NOT used?
premenopausal patients
the adverse reactions of letrozole include:
osteoporosis
hot flashes
joint pain
muscle pain
when is fulvestrant used
with ER+ post menopausal patients that no longer respond to tamoxifem or letrozole
what are the two approaches of endocrine therapy for prostate cancer?
block androgens from interacting with receptor
block production of androgens
what is the mechanism of leuprolide
GnRH superantagoinst - downregulates GnRH receptor
decreases secretion of LH and FSH and lowers androgen production by testes
what is the problem with leuprolide?
blocks testicular production of androgens but not adrenal androgen production —> castration resistant tumors
how is the problem with leuprolide solveD?
GnRH antagonist Flutamide is given to help prevent castration resistant tumors
–> causes a complete androgen blockade (CAB)
how does abiraterone work?
inhibits CYP17 which inhibits androgen biosynthesis
how do corticosteroids and adrenocortical suppression act as tumor chemotherapy?
glucocorticoids induce cell death in lymphoid tissues –> useful for treating lympholytic anemias, Hodgkins and nonHodgkins lymphomas
what is the mechanism of cortiocosteroids and adrenocortical suppressants?
bind glucocorticoid receptor which initates apoptosis by caspases
prednisone is a:
synthetic corticosteroid
adverse reactions of prednisone include:
cushingoid features, sodium retension, muscle weakness, decreased glucose tolerance, acute tumor lysis syndrome
targeted approaches include:
monoclonal antibodies
tyrosine kinase inhibitors
proteasome inhibitors
histone deacetylase inhibitors
monoclonal antibodies include:
trustuzumab (herceptin)
bevacizumab (avastin)
the mechanism of trustuzumab is
binds to exterior surface receptor on breast cancer cells (epidermal growth factor receptor type II, tyrosine kinase activity) and blocks binding of ligand
the mechanism of bevacizumab is
binds to exterior surface of VEGF receptor, blocking the signal for proliferation and angiogenesis
tyrosine kinase inhibitors include:
imatinib (gleevec)
lapatinib
the mechanism of imatinib is
inhibitor of bcr-Able, KIT, PDGF
blocks catalytic activity of tyrosine kinase by binding to ATP binding domain
substrate for CYP34A cyp2c9 cyp2d6 so potential interactions can occur between drugs metabolized by these enzymes
the mechanism of lapatinib is
inhibitor of epidermal growth factor receptor types I and II
the mechanism of bortezomib (velcade) is
inhibits 26S proteosome
metabolized by 3A4
brotezomib is used to treat
multiple myeloma
the mechanism of vorinostat (zolinza) is
HDAC inhibitor
causes accumulation of acetylated histones and induces cell cycle arrest or apoptosis of cancer cells
vorinostat is used to treat
cuaneous t-cell lymphoma (CTCL)
