Exam 1 Drugs Flashcards
1
Q
tamoxifen
A
- endocrine therapy - prodrug converted to 4-OH-TAM
- SERM
- antagoinst at breast tissue and brain
- agonist in bone and endometrium
- metabolized by CYP2D6 (so less effective with 2D6 variant
- pre & post menopausal women
2
Q
raloxifene
A
- SERM
- differs from tamoxifen because no endometrial hyperplasia
- pre & post menopausal women
3
Q
fulvestrant (faslodex)
A
- selective estrogen receptor down-modulator (SERD)
- pure ER antagonist with no agonist effects
- IM dosing
- for tx of ER+ metastatic breast cancer in postmenopausal women who have progressed on other antiestrogen therapy
4
Q
elacestrant
A
-SERD
- partial agonist at low doses and full SERD at high doses
- PO dosing
- tx of ER+ in postmenopausal women who have progressed on other antiestrogen therapy
5
Q
letrozole (femara) & anastrazole (arimidex)
A
- non-steroidal aromatase inhibitors
potent and selective inhibitor of aromatase activity - breast cancer in postmenopausal women
- 1st line therapy or indicated 3-5 years after tamoxifen
6
Q
exemestane (aromasin)
A
- steroidal aromatase inhibitor
- “suicide inhibitor” - binds irreversibly at active site and inactivates enzymes
- for breast cancer in post menopausal women who have progressed on antiestrogen therapy
- minimal toxicity - hot flashes, edema, weight gain, increased cholesterol
7
Q
leuprolide acetate (lupron)
goserelin (zoladex)
triprorelin (trelstar)
A
- GnRH analogs
- for premenopausal breast cancer
- SE : antiestrogenic effects (menopausal sx)
8
Q
gefitinib
A
- type 1 kinase inhibitor
- Inhibits EGFR by reversibly inhibiting active conformation of kinase, and cell can’t proliferate
- T790M on exon 20 causes resistance to gefitinib
- approved for NSCLC whose tumors have exon 19 or 21 L858R mutations
9
Q
erlotinib
A
- kinase inhibitor
small molecule reversible inhibitor of EGFR tyrosine kinase - competitive inhibitor of kinase, which turns off cell proliferation
- approved for NSCLC whose tumors have exon 19 or 21 L858R mutations
- SE: rash, fatigue, diarrhea
10
Q
afatinib
A
- kinase inhibitor - covalent inhibitor of all ErbB receptors
- for tx of EGFR mutant NSCLC with EGFR mutations
- screening necessary for exon 19 deletions or exon 21 substitution mutations (L858R)
11
Q
osimertinib
A
- kinase inhibitor - 3rd gen EGFR inhibitor
- covalent inhibitor
- for tx of pts with NSCLC with T790M mutant EGFR and exon 19 deletion or exon 21 substitutions
12
Q
lapatinib (tykerb)
A
- kinase inhibitor - blocks HER2 and EGFR signalling
- for tx of HER2+ breast cancer
- reversible inhibition of HER2 and EGFR
- SE: diarrhea, N/V
13
Q
tucantinib (tukysa)
A
- kinase inhibitor - small molecule tyrosine kinase inhibitor that preferentially binds to HER2
- for tx of HER2+ breast cancer
- AE less severe than lapatinib
14
Q
midostaurin
crenolanib
quizartinib
A
- FLT3 inhibitors: tx acute myeloid leukemia
midostaurin: 1st gen, type 1, broad kinase inhibitor
crenolanib: 2nd gen (more specific/potent inhibition), type 1
quizartinib: type 2, specific for ITD mutations
15
Q
imatinib (gleevec)
A
- type 2 small molecule inhibitor of ABL tyrosine kinase
- results in reduced proliferation and enhanced apoptotic cell death in CML and GIST
- toxicities: N/V, fluid retention and edema, neutropenia
16
Q
ponatinib (inclusig)
A
- kinase inhibitor - BCR-Abl inhibitor
- effective against all major mutant forms of BCR-Abl
- inhibits the “gatekeeper” mutation T315I (that is resistant t to other BCR-Abl compounds)
17
Q
alectinib (alecensa)
A
- kinase inhibitor - more specific inhibitor of ALK
- for tx of pts with anaplastic lymphoma kinase positive metastatic NSCLC who have progresses/intolerant to crizotinib
- brigatinib also approved of ALK mutations
18
Q
dabrafenib (tafinlar)
A
- kinase inhibitor - 2nd gen BRAF-V600 inhibitor
- tx w/ trametinib for BRAF-V600E/K mutant metastatic melanoma
- also for NSCLC with positive BRAF-V600 mutations
19
Q
trametinib (mekinist)
A
- kinase inhibitor - inhibits kinase activity of MEK1 and MEK2
- used in combo with dabrafenib
- type 3 allosteric inhibitor
- not indicated for pts who received prior BRAF therapy
- AE: rash, diarrhea, lymphedema
20
Q
acalabrutinib
A
- kinase inhibitor - 2nd gen covalent BTK inhibitor and targets Cys481
- more selective and potent than ibrutinib (1st gen)
- for B-cell lymphoma (MCL and CLL)
21
Q
rampamycin analogs
A
- inhibit function of mammalian target of Rampamycin (mTOR)
- mTOR is serine-threonine kinase
22
Q
everolimus (afinitor)
A
- kinase inhibitor - inhibits mTORC1
- used for advanced renal carcinoma and organ transplant
23
Q
5- fluorouracil (5-FU)
A
- anti-metabolite – pyrimidine analog- fluorinated uracil analog
- converted to FdUMP in two steps
- FdUMP mimics dUMP and binds to acitive site of thymidylate synthase, forms ternary complex with enzyme and tetrahydrofolate. traps in ternary complex and TMP can’t be produced – inhibits DNA synthesis which leads to thymineless death
- resistance: downregulation of activating enzymes that converts 5-FU to FdUMP, upregulation of thymidylate synthase
- 5% of population has gene polymorphism resulting in dihydropyrimidine dehydrogenase deficiency (breaks down 5-FU) –can predict toxicity with 5-FU
24
Q
thymidine
A
“drug rescue”
- 5-FU then thymidine rescues patient from 5-FU overdose. reduces toxicity
25
Q
leucovorate
A
- drug synergy with 5-FU
- converted to tetrahydrafolate in cell
- higher tetrahydrofolate level increases efficacy of 5-FU by increasing amount of the covalent ternary complex with thymidylate synthase
26
Q
capecitabine
A
- orally active prodrug of 5-FU
27
Q
cytarabine (cytosine arabinoside, Ara C)
A
- anti-metabolite – cytosine analog
- converted to Ara-CTP intracellularly (Ara-CTP is competitive inhibitor of DNA polymerase, also incorporated into DNA and inhibits further DNA synthesis)
- cytidine deaminase converts cytarabine to non-toxic uracil arabinoside. decreased levels of cytidine deaminase in CNS makes Ara-C highly toxic in meningeal leukemia and lymphoma (cancers in brain & spinal cord)
- resistance to cytarabine: downregulation of activating enzymes, upregulation of cytidine deaminase, downregulation of transporter to move drug into cells
28
Q
gemcitabine (difluorodexoycitidine)
A
- anti-metabolite – cytosine analog
- greater potency than cytarabine
- 2 fluoro substituents at 2’ sugar causes increased cell permeability, greater affinity for activating enzyme, better evasion of DNA repair enzymes
29
Q
tetrahydrouridine
A
- for drug synergy with cytarabine
- cytidine deaminase inhibitor
- (cytarabine is inactivated by cytadine deaminase)
- given with cytarabine to increase efficacy and decrease resistance
30
Q
6-mercaptopurine (6-MP, purenthol)
A
- anti-metabolite – purine analog
- thio analog of adenine
- inhibits multimple enzymes in de novo purine biosynthesis pathway – blocks synthesis of purine neucleotides
- resistance: loss of HGPRT (activating enzyme)
- 6-MP inactivated by TPMT – TPMT polymorphism occurs in 1-% kids
- polymorphism increases risk of toxicity (heterozygotes: 65% of standard dose, homozygotes: 10%)
- drug interaction with allopurinol: (allopurinol is a xanthine inhibitor for gout, xanthine oxidase breaks down 6-MP, so toxicity risk)
31
Q
folic acid
A
- enters as dihydrofolate and gets reduced to tetrahydrofolate by dihydrofolate reductase (DHFR)
- DHFR inhibition reduces FH4 pools, folate pools accumulate as inactive dihydrofolate (inhibits thymidine monophosphate synthesis which inhibits RNA and protein synthesis and purine/pyrimidine synthesis)
- compounds that bind to and inhibit DHFR are folate mimics
32
Q
methotrexate
A
- antifolate – DHFR inhibitor
Resistance: - amplification of DHFR gene or mutation of DHFR to resistant form of the enzyme
- decreased polyglutamation results in decreased intracellular MTX (polyglutamation of intracellular MTX helps retain MTX inside the cell)
33
Q
pralatrexate
A
- antifolate
- designed to accumulate preferentially in tumor cells
- selectively enters cells expressing reduced folate carrier type 1 (RFC-1) - which is usually overexpressed in cancer cells
34
Q
pemetrexed
A
- inhibitor of dihydrofolate reductase, thymidylate synthase, and glycinamide ribonucleotide formultransferase
- (decreased risk of drug resistance)
35
Q
leucovorin
A
- serves as folate, bypass need for DHFR
- to “rescue” normal tissues from methotrexate toxicity
- converted to tetrahydrofolate intracellularly
- increases intracellular pools of tetrahydrofolate and reverses toxic effects of DHFR inhibition (leucovorin competes with methotrexate transport in cells)
- leucovorin also enhances activity of 5-FU
36
Q
mechlorethamine
A
- alkylating agent – rapidly alkylates all nucleophiles (modifies DNA, RNA, and protein)
- SE (of all alkylators): myelosuppression, N/V, carcinogenic, teratogenic
37
Q
chlorambucil
A
- alkylating agent – mechlorethamine derivative
added aryl group to decrease nucleophilicity
38
Q
cyclophosphamide
A
- alkylating agent – prodrug - required hydroxylation by hepatic CYP450
- converted to phosphamide mustard in tumor cell
- deactivated by aldehyde dehydrogenase
- most used alkylating agent
- mild bone marrow toxicity
- hemorrhagic cystitis is dose limiting toxicity (acrolein toxic to bladder mucosa)
39
Q
mesna
A
- given with cyclophosphamide to block hemorrhagic cystitis
- accumulates in urine (bladder) and inactivates acrolein in urine
- the free thiol on mesna reacts with and inactivates acrolein metabolites in urine
40
Q
mitomycin C (mutamycin)
A
- alkylating agent – aziridine containing natural product
- forms bifunctional adducts (crosslinks)
- myelosuppression is dose-limiting
41
Q
cisplatin
A
- platinum drug – covalent crosslinker
- cross links form slower than alkylating agents
- SE: dose-limiting nephrotoxicity, N/V, minimal bone marrow toxicity
42
Q
alkylating agents and platinum drugs: resistance
A
resistance:
- increased expression of DNA repair enzymes
- increases intracellular conc of non-protein thiols, especially glutathione (thiols have high reactivity to electrophilic intermediates, so they intercept reactive intermediates of alkylating agents)
- increased expression of cellular glutathione S- transferase (GST catalyzes rxn of glutathione with alkylating agents)
43
Q
topotecan & irinotecan
A
- potent inhibitors of topo 1 – camptothecans
- prodrugs
- irinotecan is broken down to SN-38 (active metabolite)
- SN-38 metabolized by UGT1A1 – polymorphisms with low expression of UGT1A1 predict increased toxicity with irinotecan
44
Q
doxorubicin
A
- topo 2 inhibitor
- inhibits topo 2 from reattaching DNA/carrying out normal function, ds breaks, covalently attached topo 2 to DNA which blocks additional steps
- toxicity: intercalator, free radical causes DNA damage
- free radical damage causes cardiotoxicity since heart tissue has low levels of enzymes that neutralize free radicals
- activity greater in G2/M, but topo2i are not cell phase specific
Resistance: glutathione S-transferase overexpression - also in this class: daunorubicin, epirubicin, idarubicin, liposomal doxorubicin
45
Q
dexrazoxane
A
- used to manage cardiotoxicity caused by iron-catalyzed free radical formation
- binds to iron, blocks iron, oxygen induces toxicities (less free radicals bc less iron)
- no evidence of interference with antitumor effect
46
Q
etoposide
A
- topo 2 inhibitor
- blocks religation of topo 2 but no free radical formation
- does not intercalate
- G2 block-cell cycle specific
47
Q
bleomycin
A
- topo 2 inhibitor
- intercalates and forms free radicals
- radical intermediate leads to DNA ss and ds breaks
- greatest effects in G2/M phase
- toxicity: pulmonary (inflammation which leads to fibrosis) – dose limiting and cumulative
- bleomycin is inactivated by bleomycinaminohydrolase which explains pulmonary toxicity and rash SE) (bc that’s in high conc everywhere except skin and lungs)
48
Q
vincristine
A
- vinca alkaloid - very potent
- binds to tubulin and leads to inhibition of microtubule assembly & inhbits microtubule shortening
- microtubules are critical to nerve cell axon function, which is why neurotoxicity is common dose-dependent and dose limiting
- myelosuppression mild and rarely clinically significant
- also in this class: vinblastine and vinorelbine
49
Q
eribulin
A
- microtubule inhibitor – inhibits microtubule polymerization
- lower rate of neurotoxicity
50
Q
paclitaxel
A
- microtubule stabilizer – taxane
- bind to microtubules and promote assembly in bundle: decrease free tubule, and block depolymerization
- toxicity: myelosuppression - dose limiting, neurotoxicity(less so than vincas)
- also in this class: doxetaxel, cabazitaxel
- cabazitaxel has poor binding to MDR and P-glycoprotein pumps, so shows efficacy in multi-drug resistant tumors bc not rapidly pumped out of those cells
51
Q
epothilones
A
- binds to tubulin and promotes tubulin polymerization and microtubule stabilization
- more potent than taxol
- not cross-resistant with taxanes - poor PGP substrates
52
Q
trastuzumab (herceptin)
A
- recombinant humanized monoclonal antibody specific for HER2
- for treatment of breast cancer HER2+
- binds to receptor and induces antibody-dependent cellular cytotoxicity
- toxicities: flu-like symptoms, cardiomyopathy risk, no intrinsic myelosuppression but increased risk in combo with chemo, risk of hypersensitivity rxns
53
Q
pertuzumab (perjeta)
A
- recombinant humanized monoclonal antibody specific for HER2
- inhibits dimerization (inhibits kinase activity w/o antibody-dependent cytotoxicity)
- used in combo with trastuzumab
- taxant + trastuzumab + pertuzumab first line standard of care
54
Q
cetuximab (vectibix)
A
- recombinant chimeric monoclonal antibody that binds specifically to extracellular domain of EGFR
- blocks phosphorylation and activation of receptor-associated kinases
- inhibits growth and induces apoptosis
- indicated for colorectal and head and neck cancers
- toxicities: severe infusion rxn, acneiform rash, asthenias, fever
55
Q
panitumumab (vectibix)
A
- fully humanized monoclonal antibody that binds spefically to extracellular domain of EGFR
- given every 2 weeks
- SE: skin rash, diarrhea
- for tx of colorectal cancer
56
Q
bevacizumab (avastin)
A
- recombinant humanized monoclonal antibody specific for vascular endothelial growth factor (VEGF)
- no evidence as a single agent for efficacy
- used in combo with 5-FU for colorectal cancer
- bevacizumab binds the ligand, ramucirumab binds receptor
57
Q
rituxumab
A
- antibody that binds to CD20
- CD20 is transmembrand protein that regulates activation of cell cycle initiation and differentiation
- CD20 is expressed by normal B lymphocytes and immature pre-B cells (also B-cell non-Hodgkin’s lymphoma cells)
- ofatumumab is fully human monoclonal antibody for CD20
58
Q
daratumumab
A
- CD38 antibody
- CD38 is multifunctional transmembrane protein on B cells that make antibodies
- eliminates multiple myeloma cells by ADCC or CDC
59
Q
trastuzumab emtansine
A
- antibody-drug conjugate of cytotoxic agent emtansine linked to trastuzumab
- for HER2+ patients
- toxicities: (reduced bc very selective binding HER2) AE of trastuzumab, thrombocytopenia, hepatotoxicity
60
Q
trastuzumab-deruxtecan
A
- humanized anti-HER2 IgG1 monoclonal antibody
- topo1 inhibitor also
61
Q
blinatumomab
A
- BiTE that targets T cells to receptors highly expressed on cancers
- lymphoblastic leukemia
62
Q
mosunetuzumab
A
- BiTE that targets CD3 and CD20 on non-Hodgkin lymphomas
- SE: cytokine release syndrome
63
Q
ipilimumab
A
- recombinant human monoclonal antibody
- binds to cytotoxic T lymphocytes antigen 4 receptor and reverses CTL inhibition
- tx of advanced metastatic melanoma
64
Q
pembrolizumab (keytruda)
A
- monoclonal antibody that binds the program death 1 (PD-1) receptor and blocks interaction with PD-ligant 1 and 2
- PD-1 is expressed on T cells
- inhibiting inhibition of T cell signalling
65
Q
atezolizumab
A
- monoclonal antibody that binds program death ligand 1 and blocks its interaction with PD-1
- PD-L1 is expressed on macrophages and tumor cells
