Drugs Flashcards
1
Q
what do alylating agents target?
what do they cause
A
DNA
cause crosslinking
2
Q
what cycle and phase are alkylating agents a part of?
A
mechlorethamine, carmustine are cell-cycle-nonspecific • also affect Go cells
– cycle-specific phase nonspecific
• e.g. cyclophosphamide,
3
Q
what are toxic side effects fo alkylating agents.
A
naueas
alopecia
myelo supression
4
Q
what do you get typical side effects like nausea, alopecia, and myelosupression with antineoplasia drugs?
A
becuase they target the most rapidly dividing cells first.
5
Q
what is the nadir?
A
the lowest point on a chart.
lowest level in a series of levels.
6
Q
what are the nitrogen mustards.
A
Mechlorethamine Cyclophosphamide
7
Q
Nitrosoureas?
A
Carmustine
8
Q
what aklating agent for – Hodgkin’s and non-Hodgkin’s lymphoma – breast, lung, and ovarian cancer?
A
mechlorethamine
9
Q
what alklating agent is a prodrug?
A
cyclophosphamide.
activated by P450 in the liver.
10
Q
what is a toxic side effect of cyclophosphamide?
A
sterile hemmorrhagic cystitis.
11
Q
what is the halmark of carmustine?
A
it crosses the blood brain barrier well.
12
Q
what do you use carmustine to treat?
what category is it?
A
Treatment of brain tumors, multiple
myeloma, melanoma
nitrosureas. nonspecific to phase and cycle. `
13
Q
what phase are antimeatabolites specific to?
A
the S phase.
they are great for tumor s with rapid cell proliferation.
14
Q
what do different antimetabolites analogous to?
A
folate
purines
pyrimidines
15
Q
what is methotrexates mech?
A
binds to dihydrofolate reductase and stops the formation of tetrahydrofolate.
16
Q
when do you use leucovorin?
A
after giving methotrexte.
to rescue the cells.
– Leucovorin = folinic acid, a fully reduced folate that
does not require reduction by DHFR
– normal cells often have increased capacity to bring in leucovorin relative to tumor cells
17
Q
what are side effects of methotrexate?
A
• intestinalepitheliumdamage – mild diarrhea to severe bleeding
• bonemarrowsuppression • RENAL TUBULAR NECROSIS
– keep urine alkaline to limit this
• Displacesotherdrugsfromserumalbumin
18
Q
WHAT CANCERS DO YOU GIVE METHOTREXATE IN?
A
• Acute lymphocytic leukemia • Choriocarcinoma
19
Q
what is a pyrimidine analog?
A
5-FU
Cytarabine
20
Q
what is the mech of 5-FU?
A
activated in cells to FUTP which inhibits RNA synthesis and to FdUMP which interferes with thymidylate synthase, and ultimately DNA synthesis
21
Q
what cancers for 5-FU?
A
• Broad spectrum of Uses
– Stomach, colon, pancreas, ovary, head and neck,
breast, bladder
– Basal cell carcinoma
22
Q
what is the mech of cytarabine
A
• pyrimidine (cytidine) analog that competes for
phosphorylation of cytidine
• Competes for incorporation into DNA and causes chain termination
23
Q
what are some side effects of cytarabine?
A
myelosupression and neurotoxicity.
24
Q
what cancers do you use cytarabine for?
A
acute leukemias.
AML
lymphomas and head and neck cancer.
25
what are a purine analog?
mercaptopurine.
26
what is the mech of mercaptopurine/
converted in a cell to a ribonucleotide that inhibits RNA synth and DNA synth.
27
what are some side effects of mercaptopurine.?
– bone marrow depression, gradual
| – vomiting, nausea, anorexia – Jaundice
28
what cancer s would you use mercaptopurine for?
– Acute leukemias
| – Chronic granulocytic leukemia
29
what is the role of TPMT with mercaptopurine?
you need TPMT to inactivate mercaptopurine.
<1% of patients have 2 copies of nonfunctional TPMT; cannot tolerate this drug
30
Hydroxyurea
what is the mech?
where does it arrest the cell?
inhibits ribonucleotide reductase.
blocking the conversion of ribonucleotides to dNTPs, thereby preventing DNA synthesis
arrests cell in G1-Sinterface
31
what is hydroxyurea used for?
granulocytic leukemia
| head and neck cancer.
32
what drug stops the formation of tubles. by binding to tubulin.
the vinca alkaloids.
| Vincristine vs. vinblastine
33
what drug is more myelosupressive?
Vincristine vs. vinblastine
which one do you use for breast testicular and bladder cancer?
vinblastine
blastine.
34
paclitaxel.
what is the mech?
what phase does it block in?
– enhances assembly and stability of microtubules by binding to b-subunit of tubulin
it blocks in the late G2 phase.
35
what phase is most sensative to radiation?
late G2
36
what drug Can interfere with DNA repair, intensifying the effects of DNA damage by cisplatin or cyclophosphamide
paclitaxel
37
what are some side effects of paclitaxel?
– dose-limiting leukopenia
– peripheral neuropathy
– myalgia/arthralgia
38
when do you use paclitaxel?
• Useful for refractory ovarian cancer; breast cancer
– paclitaxel plus cisplatin (or carboplatin) has become a standard therapy for ovarian cancer
• OnlytumorswithhighTGF-b1respond
– Can interfere with DNA repair, intensifying the effects of DNA damage by cisplatin or cyclophosphamide
39
what kind of drug is doxyrubicin?
\
what cycle and phase?
Example of Antitumor Antibiotic
cycle-specificphasenon-specific
40
what cancers does doxcyrubicin affet?
– the most widely prescribed agent of this class – Lymphomas, breast, ovary, small cell lung
– Many others
41
one of the few drugs with some anti- angiogenic properties?
doxcyrubicin
42
what are the 3 parts to doxorubicins mech?
intercalates in DNA
causes lipid peroxidation and free radical generation
and binds to DNA and topoisomerase.
43
what is the main side effect of doxorubicin?
cardiomyopathy.
– dose-related; cumulative
– immediate or delayed
– Role for reactive oxygen species
• H2O2 normally quenched by glutathione peroxidase, but heart has little of this enzyme
• dexrazoxane can lessen cardiomyopathy by chelating Fe and preventing free radical damage
44
bleomycin
what is the mechanism?
what does it do?
has iron containing glycopeptides that bind to DNA.
causes oxidatiove liek damage to DNA causing DNA strand breakage.
45
what is the phase for bleomycin?
G2
46
what are the cancers that bleomycin treats?
• activeagainstwidevarietyofcancers
| – Germ cell tumors of testes and ovaries – head, neck, lung, lymphomas
47
what are some side effects of bleomycin?
• minimalmyelosuppression
• pulmonarytoxicity(e.g.pneumonitis,fibrosis) – dose-related
– cumulative & potentially fatal
• Skinvesiculation,hyperpigmentation
• lung and skin have lowest levels of bleomycin
hydrolase (which inactivates bleomycin)
• fever(50%),alopecia
48
etoposide
mech
bind to the topoisomerasre comples and causes dsDNA breaks that cannot be repaired.
onces the DNA breaks the etopside and DNA is bound to end.
49
when does etoposide work?
in the late G2 phase.
50
what cancers do you use etoposide for.
– Lymphomas, acute leukemia, small cell lung,
| testis, Kaposi’s sarcoma, others
51
what are biological response modifiers?
naturally occuring proteins that you can add more of to try to fight off the tumor. they will then have minimal side efffects because they are already present in your body.
52
what is a granulocyte colony stimulating factor?
filgrastim
53
what is the mech of filgrastim?
it causes there to be promotion fo the progenitors of neutrophils.
54
filgrastim side effects.
Bone pain. you are stimulating it to make more.
55
trastuzumab
what is the mechanism?
is it human?
it binds the the her2 receptor.
it is humnized.
56
what are some side effects of trastuzumab?
cardiomyopathy
hypersensativity
infusion rx:fever chills.
57
when do you use trastuzumab?
usually in cancer as a first line treatment.
and in gastroesophageal.
25% of metastatic breast cancers over express her2.
58
what is cisplatins mech?
it is a platinum drug
| where hydrolysis yeilds activated species that cause cross linking.
59
what is the specific cycle that cisplatin works in?
it is cycle specific and phase non specific.
60
what cancer do you use cisplatin to treat?
testicular cancer
ovarian cancer.
head neck bladder and many others.
61
what are some cisplatin side effets?
nephrotoxicity
ototocicity
peripheral neuropathy.
electrolyte disturbances.
nasea and vomitting
62
cis platin has the widest spectrum of action when compared to the other platins.
Carboplatin and oxaliplatin have decreased incidence of some side effects (e.g. nephrotoxicity)
• Carboplatin and oxaliplatin have narrower spectrum of action
• Oxaliplatin the best of the platinum agents at colorectal CA
– e.g. FOLFOX: leucovorin, 5-FU, oxaliplatin
63
procarbazine
| what is the mechanism?
it is activated in vivo in liver to a methylating agent that causes chromosomal damage
64
what is the use for procarbazine?
it is used for hodgkins lymphoma and has the greatest effect in the G1 and S pahse.
65
what are the uses of hormone and hormone antagonist in treating breast cancer?
• Useful against tumors that are steroid hormone- dependent
– steroid hormone receptor assays
– ~33% of all breast cancers respond to hormonal
therapy
– ~66% of breast cancers with good estrogen receptor content respond to hormonal therapy
66
what are some strategies for hormone therapy?
what are teh consequences of this approach?
give the opposite hormone.
– estrogens for prostate cancer
– progestins for endometrial tumors – androgens for breast cancer
give anti hormone compounds.
– Antiandrogens for prostate cancer – Antiestrogens for breast cancer
you have a decrease in the growth fraction of responding tumors
and more cells in the G0 phase.
67
• Responses to hormonal therapy can be dramatic and prolonged
– offer some of the most specifically tumor-directed activities of any chemotherapeutics
– but resistance can occur after prolonged use
68
• Beneficial side effects of other hormonal
| therapies:
– adrenocorticoids as antiemetics – androgens as anabolic agents
– progestins as appetite stimulants
69
what is prednisones mech of action?
what phase can it arrest cells in.
it binds to steroid receptor and depresses cell growth.
may arrest cell in the G1 phase.
– induce nucleases which may modulate cell lysis
70
what drug is lympholytic for lymphoma and leukemia.
prednisone.
71
what are the pallative effects of prednisone?
– anti-emetic, stimulates appetite – anti-inflammatory
72
what are some side efffets of prednisone?
* potentialcomplicationis immunosuppression
* At doses and duration generally used, there is limited myelosuppression
* good for combination therapy
* Maycauseweightgain,fluidretention,and psychologic effects
73
antiestrogenic drugs.
estrogen receptor antagonists?
aromatase in hibitorts that are non steroidal?
Estrogen receptor antagonists – Tamoxifen(TAM)
– Raloxifene
Aromatase Inhibitors
– Non-steroidal
• letrozole
```
• Advantages of Nonsteroidal:
– Oral, rapid onset
– Estrogenbelowdetectable
levels
– Noandrogenicsideeffects
```
74
Tamoxifen
| mechanism?
nonsteroidal antiestrogen that competitively blocks estrogen receptors in breast tissue
generally cytostatic
– cells held in Go/G1
– tumor regrows when tamoxifen removed
– Stopping cell growth without necessarily killing the cells
75
what are the uses of tamoxifen?
– advanced post-menopausal breast cancer
• adjuvant therapy
– pre-menopausal metastatic breast cancer
– breast cancer prophylaxis for women at high risk
• can reduce breast cancer risk by ~45%
76
what activates tamoxifen?
• Tamoxifen is activated by CYP2D6
77
what are the side effects of tamoxifen?
• Side effects:
– nausea, vomiting
– menopause-like symptoms
• hot flashes, vaginal bleeding/discharge
– Fatigue
– Bone & other musculoskeletal pain (back pain,
arthralgia)
– may increase rates of uterine/endometrial cancer
• 2.2 in 1,000, vs. 0.75 in 1,000 for placebo
– pulmonary or other deep emboli
• 0.75 in 1,000, vs. 0.25 in 1,000 for placebo
78
what is aromatase?
| how does it function?
it converts androgens to estrogens.
it is the major way of generating estrogen in women.
79
what drug inhibits aromatase?
Blocks conversion of androgens to estrogens by inhibiting aromatase
prevents the stimulation of growth of er cells.
80
aromatase inhibitors bind irreversibly to the heme of CYP19 (aromatase), thereby inhibiting to conversion of androgens to estrogens
thumbs up
81
what is the 1st line treatment of letrozole?
• 1st-linetreatmentofpost-menopausallocally
advanced or metastatic breast cancer
* Hormone receptor-positive or receptor-unknown
* Adjuvant treatment of postmenopausal advanced breast cancer in those who have received 5 years of adjuvant tamoxifen therapy
82
Post-menopausal women with locally advanced or metastatic breast cancer
who survived longer those on letrozole or tamoxifen?
letrozole made progression take longer . its
Bottom line: aromatase inhibitors (e.g. letrozole) are becoming bigger players in post-menopausal breast cancer
83
what does tamoxifen do to bone density?
it will not decrease it infact it might increase it.
84
what is a gnRH analog?
| what cancer would you use it for?
leuprolide
Advanced hormonally responsive prostate cancer
• Most common 1st line drug therapy
• If working, drops PSA levels to very low or
undetectable
– Unlabeled uses: breast & endometrial cancer
85
what is a non steroidal androgen receptor blocker?
flutamide
86
what is leuprolides mech of action?
• After 2-4 weeks, it desensitizes GnRH signaling, decreasing LH/FSH and decreasing testosterone to castration levels
87
leuprolide side effect?
Commonsideeffects
– hot flashes
– impotence
– disease flare in first 1-2 weeks
88
what is flutamide?
| what is it used for the treatment of?
• nonsteroidal antiandrogen that blocks androgen receptors
• Treatmentofmetastaticprostatecancer – used in combination with GnRH agonist
– or 2nd line therapy
89
what are the side effects of flutamide?
– gynecomastia, impotence
– diarrhea
– hepatotoxicity (uncommon)
90
what is the resistance to anti neoplastics?
Restingcells
• Toxiceffectspreventadequatedosing
• Spontaneousmutations
• Don’trespondtoapoptotictriggers
• Clinicalresistance
• Selection and overgrowth — major cause of chemotherapeutic failure
– most tumors will contain a small fraction (~1 in 106 cells) that are likely resistant to one drug (and related drugs)
91
what are some cellular mech anismas of drug resistance?
```
increased efflux
activate detoxifying systems
block apoptosis
activate dna repair
decrease influx.
```
92
how do you over come resistance?
you use combination therapy.
unlikely that cells are simultaneously resistant to 3 drugs, except for multi-drug resistance (MDR)
93
what is the main cause of multidrug resistance?
Mediated by ATP-dependent drug efflux
pumps
Can cause simultaneous resistance to many drugs, even those in different classes
• MDR especially prominent for:
– vinca alkaloids, e.g. vincristine, vinblastine – Antibiotics, e.g. doxorubicin, bleomycin
– etoposide
– Taxanes, e.g. paclitaxel
94
how do you get around resistance?
* Increasedose
* Multi-drugregimens
* Co-administeragentsthatdefeattheresistance
* Administer drugs whose metabolism, mechanism of action, or both are different from those used in original regimen
* Recruitcellsoutofrestingphase
95
why use combination chemotherapy?
• mainlydrivenby:
– growth kinetics of large tumors
– high probability of drug-resistant cells
96
what are the prinicples of combination therapy?
differentcellcyclespecificities
– cell-cycle-specific and nonspecific agents
• activeassingleagents
• non-overlappingtoxicities
– e.g. vincristine, prednisone, bleomycin, and L- asparaginase lack significant bone marrow toxicity
• different mechanisms of action – in some cases prove synergistic
• Optimaldoseandsequence
• Optimaltiming/intervals
```
n addition to just different mechanisms:
– Sequential blockade
– Concurrent inhibition
– Complementary inhibition – Rescue
– Synchronization
– Recruitment
```
97
what is squential blocakade?
simultaneous action of two inhibitors acting on different steps of a linear metabolic pathway
one blocks a to b and another blocks b to c.
98
Examples of Sequential Blockade
methotrexate + 5-FU
hydroxyurea and cytarabine
99
what is concurrent inhibition.
inhibitors block two separate pathways that lead to the same end product
100
complementary inhibition
what is an example of it
• one drug affects the function of an end product, the other drug affects the synthesis of that end product (or of precursors leading to its formation)
• Example:cytarabine+doxorubicin
– cytarabine inhibits DNA synthesis
– doxorubicin causes DNA damage (via intercalation & free radical generation)
101
what is an example of rescue?
“rescue” the patient's normal cells from the treatment
• Examples:
– Leucovorin (folinic acid) to rescue cells after
high-dose methotrexate exposure
– Autologous bone marrow or stem cell transplant
– ultimate form of rescue
102
what is synchonization?
what is an example of it?
Synchronize cells so they are in one phase and then use a drug that is specific for that phase
Example:
– low doses of fluorouracil to block in S phase
– then high dose cytarabine to kill in S phase
attempts to synchronize in vivo have not proven very successful
103
what is recruitment?
mobilizing slowly proliferating or non-proliferating cells to more rapid proliferation, i.e. bring cells out of Go & back into cell cycle
Therapy with cell cycle-nonspecific drugs
– e.g. alkylating agents (mechlorethamine) or nitrosoureas (carmustine)
– slowly recruit non-dividing cells into cell cycle – Then hit them with cycle-specific drugs
