16/17- Antineoplastic agents Flashcards
folate is required for the synthesis of ..,
purines
primary target of methotrexate
dihydrofolate reductase
2 actions of methotrexate
- reduces synthesis of purines
- reduces synthesis of dTMP by inhibiting the necessary cofactor for thymidylate synthetase
—> reduces cellular proliferation and induces cellular death by preventing synthesis of RNA and DNA
used to reduce methotrexate toxicity
leucovorin
MOA 5-fluorouracil
metabolised to FdUMP which inhibits thymidylate synthase
5-FU causes damage by..
decreasing levels of dTMP and by incorporating into DNA and RNA
prodrug of 5-FU taken orally
capecitabine
adverse effects 5-FU
oral and GI ulcers
bone marrow suppression
specific treatment uses for cytarabine
acute myelogenous leukemia
only used in treatment of hematologic malignancies
during what stage of the cell cycle is cytarabine active?
only active in s phase
MOA cytarabine
incorporation into DNA inhibits DNA polymerase thus halting elongation of DNA molecules
inactivates cytarabine
cytidine deaminase
toxicity of cytarabine
cerebellar syndrome because CNS is exposed to higher levels than the rest of the body
-> dysarthria, nystagmus, ataxia
what does cytarabine need in order to become activated?
nucleoside transporter and deoxycytidine kinase
cytotoxic effects of gemcitabine
- incorporated into DNA -> inhibit synthesis and function
- ihibits ribonucleotide reductase (decrease dNTPS for DNA synthesis)
what enzyme is necessary for 6TG and 6MP to act?
hypoxanthine-guanine phosphoribosyl transferase HGPRT
MOA 6-TG and 6-MP
incorporation into DNA
stop purine synthesis
MOA fludarabine
incorporated into DNA and RNA
inhibits DNA pol and ribonucleotide reductase
what enzyme is necessary to activate fludarabine?
deoxycytidine kinase
also necessary to activate cladribine
standard therapy for hairy cell leukemia
cladribine
MOA cladribine
incorporated into DNA
potent inhbitor of ribonucleotide reductase
cytotoxic MOA methotrexate
inhbits dihydrofolate reductase –> reduces precursors for RNA and DNA synthesis
cytotoxic MOA 5-FU
incorporated into DNA and RNA –> inhibts synthesis and function
inhbits thymidylate synthetase which reduces DNA precursors
cytotoxic MOA cytarabine
incorporated into DNA and RNa, which inhbits synthesis and function
inhibits DNA synthesis by inhibiting DNA polymerase
cytotoxic MOA gemcitabine
incorporated into DNA, which inhibits synthesis and function
inhibits ribonucleotide reductase which reduces precursors for DNA
cytotoxic MOA 6-MP and 6-TG
incorporated into DNA which inhibits synthesis and function
reduce precursors for RNA and DNA by inhibiting purine synthesis
cytotoxic MOA fludarabine
incorporated into DNA and RNA which inhibits synthesis and function
inhibits DNA polymerase and ribonucleotide reductase
cytotoxic MOA cladribine
incorporated into DNA
causes strand breaks
potent inhibitor of ribonucleotide reductase which reduces DNA precursors
most common binding site for alkylating agents
seven nitrogen group of guanine –> causes DNA crosslinking and strand breakage
are alkylating agents specific to a certain stage of the cell cycle?
nope - toxic in all stages
most common adverse affect of cyclophosphamide
hemorrhagic cystits
what drug is used to combat hemorrhagic cystitis of cyclophosphamide?
mesna
why is carmustine commonly used to treat brain tumors?
lipophilic and can cross BBB
3 common adverse effects of alkylating agents
can cause leukemia (4 yrs later peak incidence)
blistering properties that damage veins
bone marrow suppresion and damage to intestinal mucosa
increased expression of MGMT stops what drugs?
alkylating agents
prevents permanent DNA damage by removing alkyl groups from guanin before cross-links form
what can inactivate alkylating agents
glutathione
what transports non-classical alkylating agents into cells?
Cu2+ transporter
would you rather use cisplatin or carboplatin with another drug that cause a lot of myelosuppresion?
cisplatin
carboplatin causes more myelosuppression but less nausea, neurotoxicity, ototoxicity and nephrotoxicity than cisplatin
unique adverse effects of cisplatin
peripheral neuropathy
tinnitus
nephrotoxicity
hypomagnesia
antimicrotubule agents
vinblastine and vincristine
prevent formation of microtubules and kill in mitosis
which is more neurotoxic: vincristine or vinblastine?
vincristine has more neurological side effects but vinblastine has more significant myelosuppression
antimicrotubule agent
paclitaxel
kills in mitosis by preventing the de-polymerization of microtubules
major adverse effect of paclitaxel
peripheral neuropathy and bone marrow toxiicity
what drug is used with paclitaxel to reduce myelosuppression
filgrastim
inhibitors of topoisomerase I
irinotecan
topotecan
class II topoisomerase inhibitor
Etoposide
fuction of topoisomerases
cut DNA, unwind it, and repair the cut during DNA replication
cytotoxic antibiotics
doxorubicin
bleomycin
cytotoxic MOA of doxorubicin
intercalates with DNA –> inhibition of DNA polymerase
also inhibits topoisomerase II –> double strand breaks
unique adverse effect of doxorubicin and solution
irreversible cardiomyopathy due to free radical formation
dexrazoxane an iron chelator can reduce cardiotoxicity
MOA bleomycin
small peptide that binds to DNA and causes single and double strand breaks
what stage of the cell cycle does bleomycin affect>
causes cells to arrest in G2 pahse
what is the unique side effect for bleomycin?
pulmonary toxicity that is cumulative and irreversible BUT good news it is minimally myelosuppressive
MOA of the glucocorticoids prednisone and dexamethasone
inhbit lymphocyte proliferation
reduce intracranial pressure with brain tumors
reduce adverse effects such as nausea and vomiting
partial estrogen receptor antagonist
tamoxifen
aromatase inhbitor
anatrozole
androgen receptor antagonist useful for treatment of prostate cancer
flutamide
prevents dihydrotestosterone from binding to androgen receptors
GnRH receptor agonist
leuuprolide and goserelin
cause desensitizationof GnRH receptor on pituitary
used to treat prostate cancer
GnRh receptor antagonist
degarelix
used to treat prostate cancer
risk of tamoxifen
increase risk for endometrial cancer
what does aromatase do?
converts testosterone into estrogen
used to treat estrogen-sensitive breast tumors in post-menopausal women
anastrozole
used to treat breast cancer with Her-2 amplified
trastuzumab
blocks her-2 mediated signaling and can induce antibody dependent cytotoxicity
toxicity of trastuzumab
cardiotoxicity
used to treat EGFR expressing colorectal tumors in combination with other drugs
cetuximab
what causes tumors to be resistance to cetuximab
activating mutations in RAS
routine tests of RAS mutational status need to be preformed
binds to VEGF which prevents VEGF binding to VEGFR to promote angiogenesis
bevacizumab
used to treat colorectal and breast cancer
adverse effects bevacizumab
HTN
increased thrombosis or bleeding
increased risk GI perforation
decreased wound healing
inhibits both EGFR and HER2 kinase activity
lapatinib
use of lapatinib
used in combination with capecitabine to treat Her2, trastuzumab refractory breast cancer
first line treatment for metastatic nonsmall cell lung carcinoma
erlotinib
MOA erlotinib
EGFR inhibitor and ATP competitive inhibitor
treatment for chronic myelogenous leukemia caused by philadelphia chromosome
imatinib
inhibits the consitiutively active AL
used to treat acute lymphoblastic leukemia
asparaginase
MOA asparaginase
starve tumor cells of L-asparagine
proteasome inhibitor
bortezomib
by inhibiting the proteasome, it elevates levels of p53
adverse effects of bortezomib
thrombocytopenia, peripheral neuropathy, anemia
used to treat renal cell carcinoma
temsirolimus
MOA temsirolimus
inhibition of mTOR complex 1 reduces prtn translation, promotes cell cycle inhibition, and promotes apoptosis
NOT mTORC2 (resistant)
