Cancer drugs Pcol

Question 1

Methotrexate (MTX)

Answer 1

Antimetabolite, S phase specific
DHF analogue

MOA:
-Is a DHF analog –> it will bind to DHFR and will inhibit DHFR and will prevent conversion of DHF to THF then to MTHF
-Inhibit DNA synthesis, THF, MTHF, DHF, dTMP

Leucoverin: opposes methotrexate will increase THF and is taken up by normal cells to recover –> give one day after methotrexate

AE:
-Pulmonary toxicity
-Hepatotoxicity
-Agranulacytosis –> drop WBC
-Anemia–> drop RBC
-N/V/D –> slotting GIT
-Teratogenic
-Allopecia

Question 2

Capecitibine (oral 5-FU)
5-Fluorouracil

Answer 2

Antimetabolites, Sphase specific, dUMP analogs, inhibits synthesis of DNA, dTMP,

dUMP analogues
Inhibits Thymidylate synthase

Capecitibine is a prodrug and is converted to 5-FU
and then 5-FU is converted to 5-FUMP –> and will inhibit thymidylate synthase
therefore no conversion of dUMP to dTMP no DNA sythesis

Leucoverin –> will increase production of MTHF and need to give along with capecitibine and 5-FU because it will allow them to bind better to thymidilate synthase

Mechanism of resistance:
-Cancer cells will over-expressed thymidylate synthase
-Disrupt cell cycle, avoid apoptosis, increase efflux, decrease uptake of drug, increase metabolism of the drug

AE:
-Allopecia
-Agranularcytosis
-Anemia
-Teratogenic
-N/V/D

Question 3

Azathioprine (Im-
6-mercaptopurine

Answer 3

Antimetabolites, Sphase specific, IMP analogues, inhibit IMPDH
Prevent synthesis of DNA, IMP to AMP to dAMP to dATP
or IMP to GMP to dGMP to dGTP

Azathioprine (Imuran) is a prodrug converted to 6-mercaptopurine –> then 6-mercaptopurine is converted to 6-thioinosine monophosphate (6-TIMP) by HGPRT (hypoxanthine guanine phosphoribosyl transferase) –> and then 6-TIMP will inhibit IMPDH (inosine monophosphate dehydrogenase)

DDI:
-They are metabolize by xanthine oxidase to inactive metabolites –> so need to avoid allopurinol (xanthine oxidase inhibitor)

Mechanism of resistance by cancer cells:
-Cancer cells will over express IMPDH
-Increase efflux
-Decrease reuptake
-Avoid apoptosis
-impair cell cycle
-Increase metabolism of the drug

AE:
-N/V/D
-Hair loss
-Agranularcytosis
-Anemia
-Teratogenic

Question 4

Thioguanine

Answer 4

Antimetabolite, Sphase specific, gets incorporated in the DNA strand and causes the DNA strand to break

MOA:
-Thioguanine is activated by HGPRT into 6-thioguanine (6-TGMP) and 6-TGMP will get incorporated in the DNA strand and will cause the DNA strand to break
-No interaction with Xanthine oxidase –> so can give allopurinol

AE:
-Hair loss
-Anemia –> drop RBC
-Agranularcytosis–> drop WBC
-N/V/D

Question 5

Hydroxyurea

Answer 5

Antimetabolite, Sphase specific, Inhibits DNA synthesis

MOA:
-Hydroxurea will inhibit Ribonucleotide reductase –> so inhibit the conversion of all three ribonucleotides to deoxyribonucleotides
so no AMP to dAMP, no GMP to dGMP, no UMP to dUMP, no CMP to dCMP

-Can also be use for sickle cell –> because hydroxyurea can increase expression of fetal hemoglobin HbF and inhibit polymerization of sickle hemoglobin HbS

Mechanism of resistance: cancer cells will over expressed Ribonucelotide reductase

AE:
-Leukemia –>Longterm use of hydroxyurea
-Allopecia
-N/V/D

Question 6

Cladribine
Chlorafadine

Answer 6

Purine adenosine analogues, antimetabolites, S phase specific

MOA:
-Cladribine or chlorafadine gets incorporated into the DNA strand and will cause the DNA strand to break so no DNA synthesis and cancer cells die

Question 7

Cytarabine
Gemticitabine

Answer 7

Antimetabolites, Sphase specific,
Pyrimidine Cytidine analogues

MOA:
-Cytarabine or gemticitabine will get incorporated into the DNA strand instead of cytidine and will cause the DNA strand to be unstable and the DNA strand will break
So stop DNA synthesis so cancer cells die

Question 8

Vincristine
Vinblastine

Think Vinca Vin

Answer 8

Drug target 2: Mitosis
they are vinca alkaloids

MOA:
-They will bind to B-tubulins and will prevent the microtubules from growing - elongation onto the chromosomes –> so mitosis wont occur

Mechanism of resistance
-Cancer cells can biuld resistance by overexpressing B-tubulins or changing the structure of b-tubulins

Question 9

Paclitaxel
Dacetaxel
Nab-Paclitaxel (abraxane)

not a glycoside nor a alkaloid

Answer 9

Antimitotic agents
Taxanes (-taxel)

MOA:
Paclitaxel, dacetaxel, and Nab-Paclitaxel (Abraxane) –> will bind to B-tubulins in the microtubules and will Promote growing and elongation of the microtubules –> and the chromosomes wont be able to separate so prevent mitosis of the cancer cell

Mechanism of resistance:
-cancer cells can over express B-tubulins or change the structure of B-tubulins

AE:
-Hypersensitive rxn –> only paclitaxel and dacetaxel can cause hypersensitive rxn –> so to avoid need to give glucocorticoids or H1 -antagonist before

Question 10

Melphelan

anilino type nitrogen is less nucleophilic and is more stable so slower acting. Cycliles and forms aziridum ion that will cross link with N-G-7

Answer 10

Drug target 3: alkylating agent
Alkylation with guanine residues –> alkylates at NG7 (guanine at nitrogen 7) anc causes:
-DNS crosslink
-Abnormal pbase paring (alkylated G:T)
Guanine ring clevage
Can give injection or PO

Alkeran

Question 11

Chlorambucil

Answer 11

Drug target 3: alkylating agent
Alkylation with guanine residues –> alkylates at NG7 (guanine at nitrogen 7) anc causes:
-DNS crosslink
-Abnormal pbase paring (alkylated G:T)
Guanine ring clevage
Can give injection or PO

Leukaran

Question 12

Mechlorethamine

cyclilizes and forms aziridium ion that will crosslink with N-G-7

Answer 12

Drug target 3: alkylating agent
Alkylation with guanine residues –> alkylates at NG7 (guanine at nitrogen 7) anc causes:
-DNS crosslink
-Abnormal pbase paring (alkylated G:T)
Guanine ring clevage
Is very reactive so cannot give orally –> need to reconstite before giving

Question 13

Cyclophosphamine

cyclilizes and forms aziridium ion and crosslink with NG7

Answer 13

Drug class 3: alkylating aget
Will add alkyl groups to NG7 (guanosine at nitrogen 7) and will cause the DNA strand to become unstable so will occur:
-Crosslink
-Abnormal base paring Alkylated G:T
-Guanine ring clevage
-Purine (guanine) excission from DNA

-Cyclophosphamine is a prodrug and needs to be metabolize by CYP 450 to its active metabolites –> but as a biproduct get acrolein.
-Acrolein can accumulate in the urinary bladder and see hemorragic cystitis –> blood in urine . So to prevent need to give MESNA (mercapto- Sulfonate- NA-)

Question 14

Bendamustine

Answer 14

Drug class 3 akylating agent
MOA:
-alkylating agent add alkyl groups to guanine bases –> causes extensive DNA damage and inhibits mitotic checkpoints and prevents DNA repair so causes apoptosis of the cancer cell

Question 15

Cisplatin
Carboplatin
Oxaliplatin

Answer 15

Drug class 3 alkylating agents
MOA:
-when crosslink with N-G-7 (guanine G-7) and incorporate the platinum to the DNA–> it will make the DNA strand very stable and causes the Cancer cell to die

AE:
-Cisplatin –> short half life is unstable –> can accumulate and kill proximal convulated tubule cells and cause nephrotoxicity. also causes neurotoxicity –> tingeling and ototoxicity

Carboplatin –> more stable but causes nephrotoxicity

Oxoplatin –> acute neurotoxicity -_> exacerbate in cold temp

Question 16

Bleomycin

Answer 16

Drug class 3 alkylating agent

MOA:
-Is a natural compound that will react with Iron and will form a complex Bleomycin-FeIII-OOH –> and will release ROS (reactive oxidative species) that will cayuse extensive DNA damage

AE: are irreversible and cummulative
-Pulmonary fibrosis
-Skin ulceration
Max liftime dose is 400 units

Bleomycin hydrolase:
-Will cause hydrolysis of bleomycin and will inactivate bleomycin–> but bleomycin hydrolase has limit quantities in the skin and lungs

Question 17

Irinotecan
SN-38

Answer 17

Drug class 4: DNA repair (non target)
Camptothecins
Topoisomerase 1 inhibitors

MOA
-Irinotecan is a prodrug and is converted to SN-38 that is the active metabolite is very lipophilic and highly protein bound

Normally topoisomerase 1 will break the DNA strand and then will reseal the strand for allow the second strand to pass
-But SN-38 will inhibit topoisomerase 1 from resealing the broken DNA strand so the cancer cell will not survive

-SN-38 is inactivated by UGT1A1 –> and UGT1A1 is highly polymorphic and if the pt has *1 is normal wild type no prob. But if the pt has *28 they have low levels of UGT1A1 and will not be able to metabolize SN-38 to inactive so the levels of SN-38 will accumulate and pt will suffer from severe AE such as neutropenia and diarrhea

AE:
-Bone marrow suppression
-GI toxicity
-Life threating diarrhea

Question 18

Etoposide

Glycoside analogue sugar +non sugar

Answer 18

Drug target 4 DNA repair (non - target)
Topoisomerase 2 inhibitor

MOA:
-Etoposide will inbibit topoisomerase 2 and will cause DNA double strand scission –> inhibit healing of DNA –> therefore leading to cell death

-Can be combine with other drugs that cause direct DNA damage for synergi

AE:
-Bone marrow suppression

Question 19

Doxorubicin
Danorubicin

Answer 19

Drug target 4: DNA repair non target anthracyclines

MOA:
-Doxorubicin and danorubicin will react with iron and will produce free radicals reactive oxidative species –> and the reactive oxidative species will cause lipid peroxidation and the cancer cell die

-They are primary excreted via bile –> so need dose adj in liver dysfunction

AE:
-Cardiotoxicity –> because the ROS are produce in the myocardium and causes lipid peroxidation in the cardiac tissue; therefore causing the cardiac tissue to become fibrotic and can cause heart failure

-Because the AE are irriversible and cummulative –>Lifetime limit dose is 550mg/m2 based on pt surface area
-Need to do a REMS and check pt medication history and PMH

Dexrazoxane –> is a cardioprotective drug is given separate with doxorubicin and danorubicin. Dexrazoxane will chelate with iron so prevent the free radicals ROS production. But it can decrease the anticancer effects of doxorubicin and danorubicin . So you need to balance the pt anticancer effect, cardiotoxicity and cardioprotective

Catalase –> is a antioxidant enzyme that will convert hydrogen peroxide H2O2–> into H2O and O2

Question 20

Abiraterone

Answer 20

Drug target 5 Hormones

Inhibit steroidogenesis

MOA:
-Abiraterone inhibit CYP 17 in the adrenal cortex. So inhibit the production of endogenous hormones like testosterone including DHT

Thera:
-Opposes the growth of prostate cancer

Question 21

Anastrozole
Letrozole
Exemestane

Think ANAs Le Exe = Anastrozole Letrozole Exemestane

Answer 21

Drug target 5 : hormones

Aromatase inhibitors

MOA:
-Inhibit the conversion of testosterone to estrogen
So opposes the unregulated growth of breast and uterus

Question 22

Fulvestrant (Fas-)
Elacestrant (Ors-)

Answer 22

Fulvestrant (Faslodex)
Elacestrant (Orsedu)

SERDS
Drug target 5: Hormones

MOA:
-It will bind to the alpha estrogen receptor and will cause a confimational change and will expose the receptor to the proteolytic enzymes and the proteolytic enzymes will bind and destroy the receptor

Opposes the growth of the estrogen dependent tissue the breast and uterus so treat breast cancer and uterus cancer

Question 23

Tamoxifene

Answer 23

Tamoxifene (Nolvadex)

Drug class 5: target hormone

MOA:
-Antagonist at breast tissue
Partial agonist at utrerus and bones

Tamoxifene is metabolize by CYP 2D6 to active metabolite endoxifen
If pt is ultra rapid –> can give it and can give SSRI
If pt is rapid wild type –> can give it but dont give SSRI
If pt is intermediate –> dont give it
If pt is poor –> dont give it

Thera:
-Can treat brest cancer

AE:
-Hot flashes
-Increases growth of the uterus –> increases risk of uterus cancer

Question 24

Erlotinib –> r
Afatinib–> i

Answer 24

Drug target 6 signals transduction (targeted)

EGFR inhibitors

MOA:
-tinib –> they are small particle drugs that will enter the cancer cell and reversible inhibits EGFR —>erlotinib
Afatinib –> irriversible inhibits EGFR and overcome the resistance

Mechanism of resistance:
-Cancer cells will mutate the T790M and Erlotinib wont be able to bind. But Afatinib will be able to overcome the resistance

AE of all EGFR inhibitors:
-Aceniform acne and diarrhea

Question 25

Lapatinib

Answer 25

Drug target 6: Signal transduction (targeted) EGFR -HER2 dual inhibitor MOA:- tinib -Small particle that can enter the cancer cells and will inhibit EGFR and also HER2 -So no downstream effects so no Proliferation, angiogenesis, metastasis AE: of all EGFR inhibitors -Aceniform and diarrhea

Question 26

Panitumumab Cetuximab (think Pani Cetu EGF)

Answer 26

Drug target 6: Signal transduction (Targeted) EGFR inhibitor MOA: -Monoclonal antibodies against EGFR against the ligand binding site --> so prevent EGF from binding --> therefore prevent the down stream effects of the tyrosine kinase receptor --> so no proliferation, no angiogenesis, no metastasis Mechanism of resistance: -Cancer cells will mutate KRAS and will be able to bypass EGFR blockade AE: -Aceniform rash and diarrhea

Question 27

Pertuzumab (humanized) Trastuzumab (Humanized) Think PeTra Her

Answer 27

Drug target 6: Signal transduction (targeted) HER2 inhibitor MOA: -Monoclonal antibody block HER 2 receptor and prevent ligand HER from binding AE: -Cardiotoxicity

Question 28

Bevacizumab

Answer 28

Drug target 6: Signal transduction (Targeted) VEGF/VEGFR inhibitor VEGF (Vascular Endothelial Growth Factor) MOA: -Bevacizumab is a monoclonal antibody against VEGF so prevent VEGF from binding -Normally the cancer cells will overexpressed VEGFR (oncogene) for VEGF (oncogene protein) to bind and activate VEGFR --> activation of VEGFR will cause endothelial cells to grow (endothelial cells line the blood vessels) and promote angiogenesis in cancer cells --> so more blood vessels around cancer cells -But bevacizumal will inhibit that AE: -Vessel injury , bleeding --> Bevacizumab will affect the quality of normal blood vessels in the body and cause blood vessel injury to normal blood vessels -Proteinurea--> protein in urine because the blood vessels are leaky -Hypertension --> normally the endothelial cells will release NO and NO causes vasodilation --> but because bevacizumab block the blood vessels to work properly so results in less NO release so less vasodilation and more vasoconstriction so increases BP

Question 29

Sunitinib Sorafenib Regorafenib Ponatinib Dasatinib

Answer 29

Drug target 6: signal transduction (Targeted) Multikinase inhibitors MOA: -Small molecules get inside the cancer cell and prevent phosphorylation of the tyrosine kinase receptor so prevent the downstream signal --> so no proliferation, no angiogenisis, no mitosis -Sunitinib --> can also inhibit cKIT --> cKIT is involve in the production of melanin and melanin provide pigmentation to the hair and skin. But inhibition of cKIT will result in no melanin so skin and hair depigmentation -When the pt is on "off-period" not taking the drug --> see pigmentation of hair and skin AE: -Vessel injury, bleeding and proteinurea --> they inhibit VEGFR so will cause damge to normal blood vessels -Hypertension --> inhibiting VEGFR in normal blood vessels will cause damage to the endothelial cells that line the blood vessels so less NO release --> less vasodilation more vasoconstriction see increase in BP

Question 30

Alecitinib Ceritinib Crizotinib Think: AleCeCrizo

Answer 30

Drug target 6: Signal transduction (Targeted) EML4-ALK tyrosine kinase inhibitors ALK is a oncogene receptor tyrosine kinase -Normaly EML4 and ALK are separated -But in a cancer patient EML4 will translocate and combine with ALK producing EML4-ALK fused protein --> and when EML4 is fused with ALK --> will result in constant activation of ALK so constant phosphorylation of the tyrosine kinase receptors so cancer cells continue to grow MOA: of AleCeCri -Alecitinib, Ceritinib, Crizotinib --> they will get into the cancer cell and will prevent phosphorylation of the EML4-ALK fused protrein Mechanism of resistance: -Cancer cells will overexpress EML4-ALK fused protein

Question 31

ANI Da Pon Asciminib Nilotinib Imatinib (Gleevec) Dasatinib Ponatinib Think: Ani Da Pon

Answer 31

Drug target 6: Signal transduction (Targeted) BCR-ABL Inhibitors BCR- Break point cluster region protein ABL- oncogene tyrosine kinase receptor In cancer pt BCR will translocate and fused with ABL --> and the fused BCR with ABL will cause constant activation of ABL so constant phosphorylation of the tyrosine kinase receptor MOA: Ani Da Pon Ansciminib, Nilotinib, Imatinib, Dasatinib, Ponatinib They will get into the cancer cell and will inhibit BCR-ABL fused protein so prevent phosphorylation so stop the downstream signaling Mechanism of resistance: -Cancer cells will over expressed BCR-ABL fused protein

Question 32

Pablociclib

Answer 32

Drug target 7: additional mechanism (targeted) CDK (cyclin dependent kinase) inhibitor Inhibits CDK4/6 --> so inhibits cell cycle progression from Gi to S phase

Question 33

Everolimus (Z-, Aff-)

Answer 33

Everolimus (Zortess, Affinitor) Drug target 7 mTOR inhibitor (mamalian Target Of Rapamycin) MOA: -Inhibits mTOR --> so stops cancer cell proliferation , survival , angiogenisis AE: -Hyperglycemia -Hypercholesterolemia -Reduction in WBC

Question 34

AcalaBRUtinib iBRUtinib ZanoBRUtinib

Answer 34

Drug target 7 Burton's Tyrosine Kinase inhibitors (BTK) When the antigen binds to BCR (B cell antigen receptor) it will cause activation of BTK --> and activation of BTK will result in phosphorulation so increase the downstream effect --> so B cell will start to proliferate in a uncontrolled manner and cause leukemia but AcalaBRUtinib, iBRUtinib, ZanoBRUtinib --> will get inside the B cell and will inhibit phosphorylation of BTK --> and decreases B cell activation therefore causes apoptosis

Question 35

Idelalisib Copanlisib Duvelisib

Answer 35

Drug target 7: targeted PI3K inhibitors (-Lisib) So prevent cancer cell proliferation and survival

Question 36

Rituximab (Rituxan) Obinutizumab

Answer 36

Drug target 8 Anti CD20 mABs CD20 a complement dependent glycoprotein in the surface of B cell and causes B cell to grow but Rituximab and obinutizumab will bind to CD20 and will cause a CDC (Complement dependent Cytotoxicity) + ADCC (Antibody Dependent Cell mediated cytotoxcity) --> causing the B cells to die AE: -Immunosuppression because B cells die -Rash

Question 37

131I Tositumomab

Answer 37

Drug target 7: anti CD20 mAB mAB against CD20 on surface of B cell and 131I radioactive idodide assist in killing of B cells AE: -Immunosuppression -- because B cells are killed -Hypothyrodism --> because 131I will release beta particles and cause killing of the thyroid cells and is permanent damage

Question 38

90Y Ibratumomab

Answer 38

Drug target 7 anti CD20 Ibratumomab will carry the radioactive lithium 90Y to the site of action CD20 and only 90Y will kill the B cells

Question 39

Loncastuximab

Answer 39

anti CD19 antibody

Question 40

Brentuximab

Answer 40

Drug target 7 anti CD30 mAB Brentuximab is a monoclonal antibody against CD30 on surface of B cell and T cell --> and will cause a antibody dependent cell mediated toxicity and B cell and T cell die Brentuximab is conjugated with MMAE (antimitotic agent) MMAE will prevent microtubles from growing Black box warning: PML - progressive multifocal leukoencephalopathy --> confusion lethargy, difficult walking, difficult speaking

Question 41

Nivolomab Pembroluzumab

Answer 41

Drug target 7: anti PD1 Anti cancer T cells have PD-1 receptor (programmed cell death receptor) and will kill cancer cells when it gets activated When PDL binds to PD-1 it will cause inactivation of the PD-1 receptor so no cell death Therefore cancer cells will produce more PDL in order for them to escape the T cell attack But Nivolomab and Pembroluzumab will antagonize PD-1 receptor and prevent PDL from binding so the Anti Cancer T cells will remain active and cause apoptosis of cancer cells AE: -Rash