Oncology Drugs- MOA

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Cyclophosphamide

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1

Cyclophosphamide

  • Alkylating agent

  • Alkylation of nucleophilic sites leading to cross-linking of DNA that’s hard to repair

  • Acrolein is a toxic metabolite!

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2

Cisplatin/Oxaplatin

  • Platinum analogs

  • Intra/interstrand cross-linking of cisplatin to DNA inhibits S phase replication and activate p53 tumor suppressor, activates pro-apoptotic proteins

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3

Methotrexate

  • Anti-metabolite, DHF analog

  • Inhibition of purine & pyrimidine synthesis via competitive inhibition of DHFR

  • Methotrexate becomes polyglutamate via FPGS, which is unregulated in tumor cells, and increases resident time in cells

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4

5-FU

  • Anti-metabolite

  • deprive cell of thimidylate synthase, no TTP, and the cells starve

  • Decreased DPYD function puts patient at risk of toxicity

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5

Capecitabine

  • Anti-metabolite

  • Pro drug metabolized by carboxylesterase to 5-DFCR and then by cytidine deaminase to 5-DFUR

  • 5-DFUR is metabolized within tumors to 5-FU by thymidine phosphorylase

  • Targets cancer more preferentially than 5-FU

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6

Cytarabine

  • Anti-metabolite

  • Deoxycytidine analog that works in S-phase, into ara-C that acts as a competitive inhibitor of DNA pol to inhibit DNA synthesis

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Gemcitabine

  • Anti-metabolite

  • Deoxycytidine analog that works in S-phase, acts a competitive inhibitor of DNA polymerase to inhibit DNA synthesis

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8

6-MP

  • Purine antagonist

  • 6-MP is converted into 6-TGNs via HPRT, 6-TGN is incorporated into DNA to arrest replication and trigger cell death

  • Deficiency in TPMT increases toxicity risk

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9

Vincristine/Vinblastine

  • Mitotic inhibitor, vinca alkaloids

  • Binds to beta-tublin to decrease microtubilin formation and carry out mitotic arrest

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Paclitaxel/Docetaxel (& Abaxane)

  • Mitotic inhibitor, taxane

  • Binds to beta-tublin to decrease microtubilin formation and carry out mitotic arrest

  • EXTENSIVE P450 METABOLISM

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11

Ixabepilone/Eribulin

  • Mitotic inhibitors

  • Microtubule stabilizers

  • Eribulin is a subunit sequestrant

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12

Irinotecan

  • Topoisomerase I inhibitor

  • Irinotecan to SN-38 via carboxylesterase

  • Maintain knotting of DNA, triggers apoptosis

  • UGT1A1 deficiencies will increase toxicities

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13

Etoposide

  • Topoisomerase inhibitor

  • Stabilize Topo II/DNA complex by preventing re-sealing of cleaved DNA and can interfere with replication and transcription

  • Accumulation of DNA strand breaks

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Doxorubicin/Daunorubicin

  • Anthracyclines

  • Intercalation into DNA helix, formation of oxygen radicals, inhibit DNA/RNA synthesis and inhibit Topo II

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15

Bleomycin

  • Anthracycline

  • Iron binding, oxygen radical generation, DNA strand breaks, and chromosomal damage

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16

Leuprolide and Goserelin

  • GnRH receptor agonist

  • Lowers testosterone after initial an initial up regulation to reduce stimulation of androgen-sensitive cancer cells, negative feedback loop

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17

Degarelix

  • GnRH receptor antagonist

  • Lowers testosterone levels as a competitive inhibitor of the GnRH receptor to reduce stimulation of androgen sensitive cancer cells, trigger apoptosis

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18

Flutamide and Bicalutamide

  • Non-steroid competitive inhibitors of androgen receptor, block androgen receptor activity and inhibit transcription of androgen receptor genes

  • Increase in estrogen levels = risk for gynecomastia

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Enzalutamide

  • Non-steroid competitive inhibitor of androgen receptor that reduces transcription of androgen receptor genes

  • Second generation, higher affinity for AR than Bicalutamide

  • DO NOT GIVE WITH CYP2C8 AND CYP3A4 INHIBITORS

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Abiraterone

  • Androgen synthesis inhibitor

  • A progesterone derivative use to inhibit 17-alpha-hydroxylase irreversibly to reduce testosterone production

  • Need to look at CYP17 activity

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21

Anastrozole/Letrozole

  • Estrogen synthesis inhibitor

  • Non-steroidal aromatase inhibitors for the treatment of HR+ BC, decreased estrone/estradiol

  • Bind reversibly to heme

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22

Exemastane

  • Estrogen synthesis inhibitor

  • Steroidal aromatase inhibitor that irreversibly inactivates aromatase via reactive intermediate formation

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23

Tamoxifen/Raloxifene

  • SERMs

  • Antagonists in breast tissue, to inhibit cell proliferation

  • Agonist in uterine tissue, increased risk of uterine cancer

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Megestrol

  • Progesterone derivative that inhibits pituitary gonadotropin release

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25

Fulvestrant

  • SERDs

  • Estrogen receptor antagonist, degradation of estrogen receptor by stimulating ubiquitnylation

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Rituximab

  • CD20 receptor antibody

  • Chimeric mAb, triggers direct Ab-dependent cellular toxicity

  • Risk of allergic response

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Obinutuzumab/Ibritumomab

  • CD20 receptor antibody

  • 1: fully humanized mAb derivative of rituximab engineered to increase binding to effector cells

  • 2: radiolabeled rituximab conjugate with higher complete remission, hard to use

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Ibrutinib

  • Non-receptor TKI, potent inhibitor of Btk, inhibits downstream PLC gamma

  • Btk is unregulated in cancer & stimulates NF-KB, stimulates cell survival

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Bevacizumab

  • VEGF TKI

  • Binds VEGFR to prevent VEGF binding, ultimately prevent angiogenesis

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Sorafenib/Sunitinib

  • Inhibitors of VEGFR, blocks ATP binding to kinase

  • Short circuit internally

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Cetuximab

  • EGFR TKI

  • Ab directed against EGFR to inhibit receptor signaling

  • Chimeric precursor

  • KRAS mutation means these drugs won’t work

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Eriotinib (1st)/Afatinib (2nd)/Osimertinib (3rd)

  • EGFR TKI’s

  • Erotinib: reversible binder of EGFR

  • Afatinib & osimertinib: irreversible EGFR binder

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Lapatinib

  • HER2 Signaling targets

  • Reversible inhibitor of RTK, block HER2 and EGFR

  • Blocks ATP binding site

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Trastuzumab

  • HER2 Signaling targets

  • Bind receptor, trigger antibody cell toxicity, short circuit ability of receptors to dimerize and signal

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Enhertu

  • New HER2 signaling target

  • New, Ab-drug conjugate

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Imatinib

  • Bcr-Abl TKI

  • Binds ATP pocket in Bcr-abl where it stabilizes a catalytically inactive form of the enzyme, relatively specific

  • Given chronically, T3151 mutants prevent imatinib binding

  • Others: Ponatinib for T3151 mutations, nilotinib, dasitinib

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37

Midostaurin

  • FLT3 TKI

  • Small molecule inhibitor of FLT3 that prevents dimerization of the receptor to silence downstream signaling associated with cancer cell proliferation

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38

Bortezomib

  • Proteasome inhibitor, serine protease

  • Regulation of protein content by protease-mediated degradation of target proteins

  • Generally prevent the degradation of pro-apoptotic proteins

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Carfilzomib

  • Proteasome inhibitor

  • Irreversibly inhibits threonine protease activity of proteasome

  • Regulation of protein content by protease-mediated degradation of target proteins

  • Generally prevent the degradation of pro-apoptotic proteins

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40

Ivosidenib

  • Cell differentiation inducer

  • Push cancer cells into differentiated cell

  • Metabolized by CYP3A4, caution with inducers/inhibitors

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Nivolumab

  • Anti-PD 1 mAb

  • Binds PD-1 instead of ligand binding & transmitting a signal to T-cells to prevent killing of cancer cell

  • Enables T-cell to kill of the cancer cell

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43

Pembrolizumab

  • Anti PD1 mAb

  • Breaks the connection between tumor cell and T-cell, allows T-cell to do its job in mediated tumor cell death

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44

Durvalumab, Avelumab, Atezolizumab

  • PD-L1 mAb

  • Bind PD-L1 instead of PD-1, allow T-cell to do its job in mediated tumor cell death

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45

CAR-T Therapy

  • Based on engineering immune cells to recognize cancer cell specific antigens, targeting and destroying them

  • Circumvent immunogenicity

  • “Living drug”

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