16/17- Antineoplastic agents Flashcards by Elle B

folate is required for the synthesis of ..,

purines

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primary target of methotrexate

dihydrofolate reductase

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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

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used to reduce methotrexate toxicity

leucovorin

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MOA 5-fluorouracil

metabolised to FdUMP which inhibits thymidylate synthase

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5-FU causes damage by..

decreasing levels of dTMP and by incorporating into DNA and RNA

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prodrug of 5-FU taken orally

capecitabine

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adverse effects 5-FU

oral and GI ulcers

bone marrow suppression

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specific treatment uses for cytarabine

acute myelogenous leukemia

only used in treatment of hematologic malignancies

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during what stage of the cell cycle is cytarabine active?

only active in s phase

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MOA cytarabine

incorporation into DNA inhibits DNA polymerase thus halting elongation of DNA molecules

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inactivates cytarabine

cytidine deaminase

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toxicity of cytarabine

cerebellar syndrome because CNS is exposed to higher levels than the rest of the body

-> dysarthria, nystagmus, ataxia

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what does cytarabine need in order to become activated?

nucleoside transporter and deoxycytidine kinase

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cytotoxic effects of gemcitabine

incorporated into DNA -> inhibit synthesis and function

- ihibits ribonucleotide reductase (decrease dNTPS for DNA synthesis)

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what enzyme is necessary for 6TG and 6MP to act?

hypoxanthine-guanine phosphoribosyl transferase HGPRT

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MOA 6-TG and 6-MP

incorporation into DNA

stop purine synthesis

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MOA fludarabine

incorporated into DNA and RNA

inhibits DNA pol and ribonucleotide reductase

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what enzyme is necessary to activate fludarabine?

deoxycytidine kinase

also necessary to activate cladribine

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standard therapy for hairy cell leukemia

cladribine

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MOA cladribine

incorporated into DNA

potent inhbitor of ribonucleotide reductase

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cytotoxic MOA methotrexate

inhbits dihydrofolate reductase –> reduces precursors for RNA and DNA synthesis

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cytotoxic MOA 5-FU

incorporated into DNA and RNA –> inhibts synthesis and function

inhbits thymidylate synthetase which reduces DNA precursors

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cytotoxic MOA cytarabine

incorporated into DNA and RNa, which inhbits synthesis and function

inhibits DNA synthesis by inhibiting DNA polymerase

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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)