Pharm P3 Fall Exam 2---L8, 9, 10

Front 1

"o"mab
"xi"mab
"zu"mab
"u"mab

Back 1

o = mouse monoclonal antibody
xi = chimeric monoclonal antibody
zu = humanized monoclonal antibody
u = human monoclonal antibody

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tyrosine kinase inhibitors (TKI) MOA

"-inib"

Back 2

competatively bind to ATP-binding pocket and inhibit their kinase activity

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26S proteosome inhibitor

"-omib"

Back 3

Inhibition of a chymotrypsin-like proteolytic activity of the 26S proteasome activity

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bortezomib..MOA and AE. what type of cancers?

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reversible inhibitor of 26S proteosome (specifically chymotrypsin)

multiple myelomas and lymphoma
inhibits degradation of ubiquinated proteins including tumor suppressors (so increased conc. of tumor suppressors)

AE: thrombocytopenia, neutropenia, anemia

Front 5

explain PI3K pathway of tyrosine kinase receptors

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PI3K = SURVIVAL!!

PIP3 activates AKT by facilitating its phosphorylation by PDPK1 and PDPK2 (mtorC2).

AKT, in turn, activates mTOR which creates proteins for cell growth, proliferation, and survival.

PTEN regulates activity of the PI3K pathway by converting PIP3 back to PIP2.

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explain MAPK pathway of tyrosine kinase receptors

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MAPK = PROLIFERATION!

RAS, RAF, MEK, and ERK are activated by sequential kinase activity. Both the pathways regulate multiple cellular processes vital for the malignant cell.

Ligand binding and, therefore, downstream activation are blocked by EGFR MoAb. The most common aberrations leading to inappropriate activation of the pathways in cancer cells are also depicted.

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anti EGFR therapies: monoclonal antibodies

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cetuximab, panitumumab

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small molecule inhibitors (TKI)

Back 8

lapatinib, erlotininb, gefitinib

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mAb side effects:

Back 9

infusion related: fever, chills, rigor, hypotension
allergic reaction: urticaria, SOB, angioedema, bronchoconstriction

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cetuximab MOA and types of cancer

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human chimeric antibody

stimulates receptor internalization of EGFR and inhibits activation of EGRF

head and neck cancer
metastatic colon cancer

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cetuximab AE

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hypersensitivity rxn (urticaria, bronchospasm, hypotension)

rash (grade 3-4)

N/V/D

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panitumumab MOA and types of cancer

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humanized antibody = HUGE ADVANTAGE of decreased AE

stimulates EGFR receptor interalization

for pt that fail 5FU, irotcan or oxaliplatin chemo regimens

metastatic colorectal cancer

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panitumumab AE:

Back 13

grade 3 or 4 acne form rash

diarrhea, abdominal pain
electrolyte depletion

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erlotinib MOA, cancers, and AE

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targets kinase domain of EGFR and doesn't allow crossphosphorylation of the receptors

advanced nonsmall cell lung cancer as monotherapy

combination therapy for advanced pancreatic cancer

AE: diarrhea, rash

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her2/neu target therapy

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trasuzumab, lapatinib

all normal epithelial cells contain 2 copies of HER2

cancer caused by increase in HER2 receptors

homo- and hetero-dimerization = activation and signal cascade

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trastuzumab MOA and cancers

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recombinant humanized mAb

binds to extracellular domain of HER2 and inhibits dimerization and internalization

breast cancer

**black box warning = can cause cardiomyopathy

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lapatinib MOA and cancers and AE

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multikinase inhibitor of HER2 and EGFR

for metastatic breast cancer

AE: diarrhea, hand and foot syndrome, nausea, rash, vomiting, and fatigue

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bevacizumab MOA and cancers

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humanized mAb to VEGF

binds VEGF and inhibits its binding to VEGFR = inhibits , endothelial cell proliferation, invasion, migration, and survival.

metastatic colorectal cancer, NSCLC, metastatic breast cancer, meastatic renal cell carcinoma (RCC), glioblastoma (GBM)

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bevacizumab AE

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***blackbox warning for GI perforation

hypertension, arterial thrombotic events, proteinuria, surgery and wound healing complications, hemorrhage

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sunitinib MOA and cancers

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multikinase inhibitor of VEGFR2, PDGFR, cKit, FGFR
Inhibits angiogenesis and cell proliferation

Gastrointestinal stromal tumor (GIST) after failure of imatinib
metastatic renal cell carcinoma

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sorafenib MOA and cancers

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Multikinase inhibitor that targets Raf, MAPK, VEGFR2, PDGFR
Anti-proliferation and -angiogenesis by dual inhibition of the raf kinase pathway and the VEGFR pathways


Metastatic renal cell carcinoma
Liver cancer

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sorafenib AE

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fatigue, weight loss, rash/ desquamation, hand-foot skin reaction, alopecia, diarrhea, anorexia, nausea and abdominal pain.

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chronic myelogenous leukemia (CML)

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starts in bone marrow and spreads to spleen and liver

philadelphia chromosome

BCR-ABLE genes = CML

chronic phase (CP), accelerated phase (AP) and blast crisis (BC), leading to metastasis and organ failure (lung, liver, spleen).

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bevacizumab AE

Back 24

***blackbox warning for GI perforation

hypertension, arterial thrombotic events, proteinuria, surgery and wound healing complications, hemorrhage

Front 25

sunitinib MOA and cancers

Back 25

multikinase inhibitor of VEGFR2, PDGFR, cKit, FGFR
Inhibits angiogenesis and cell proliferation

Gastrointestinal stromal tumor (GIST) after failure of imatinib
metastatic renal cell carcinoma

Front 26

sorafenib MOA and cancers

Back 26

Multikinase inhibitor that targets Raf, MAPK, VEGFR2, PDGFR
Anti-proliferation and -angiogenesis by dual inhibition of the raf kinase pathway and the VEGFR pathways


Metastatic renal cell carcinoma
Liver cancer

Front 27

sorafenib AE

Back 27

fatigue, weight loss, rash/ desquamation, hand-foot skin reaction, alopecia, diarrhea, anorexia, nausea and abdominal pain.

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chronic myelogenous leukemia (CML)

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starts in bone marrow and spreads to spleen and liver

philadelphia chromosome

chronic phase (CP), accelerated phase (AP) and blast crisis (BC), leading to metastasis and organ failure (lung, liver, spleen).

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imatinib (1st gen) MOA

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for CML

inhibits BCR-ABL and other TK's

do not take other drugs with imatinib!!n

binds to ATP binding pocket of kinase domain and inhibit tyrosine phosphorylation

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imatinib AE

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myelosuppression, edema and fluid retention, severe congestive heart failure, GI bleeding, hypothyroidism, GI proliferation, renal + liver + cardiac toxicities in long term

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nilotinib (2nd gen) MOA and AE

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BCR-ABL receptor antagonists for those resistant to imatinib. CML.

AE: rash, elevated LFT, hyperglycemia, hypercholsterolemia, HA

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desatinib (2nd gen) MOA and AE

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BCR-ABL receptor antagonists for those resistant to imatinib

AE: N/V/D, GI bleeding, edema/fluid retention, fatigue, HA, rash

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alemtuzumab MOA and cancer?

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humanized Ab

binds to CD52 on T and B cells, tonsils, thymocytes, monocytes, macrophages. induced apoptosis

for b-cell chronic lymphocytic leukemia

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rituximab MOA and AE

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chimeric antibody

binds to cd20 on b cell lymphoycytes and non-hodgkin lymphoma

AE: infection, thrombocytopenia,lung toxicity, dyspnea