Flashcards in Exam 2- 3/4/5 Deck (50):
1
3 types of SMKI
tyrosine kinase, serine/threonine kinase, and lipid kinase inhibitors
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tyrosine kinase inhibitors
acting on Bcr-Abl, EGFR,
imatinib and erlotinib
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serine/threonine kinase inhibitors
acting on B-raf
vemurafenib and trametinib
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lipid kinase inhibitor
acting on PI-3K
idelalisib
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mechanisms of tyrosine kinase activation include
genetic alteration, gene amplification, point mutation, protein accumulation
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irreversible inhibition
SMKI forms a covalent bond with the cysteine residues in the active site of a protein kinase
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reversible inhibition
type inhibition I to IV
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group 1: targeting Bcr-Abl oncoprotein in chronic myeloid leukemia
imatinib (1st generation), nilotinib (2nd generation)
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major cause of CML
the philadelphia chromosome (fusion of 9 and 22)
- this one mutation leads to cancer
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imatinib clinical indication
- PH+ CML in blast crisis, accelerated phase or chronic phase after IFN therapy
- pediatric patients with PH+ CML in chronic phase
- PH+ ALL
- Kit+ GI stromal tumors (GIST)
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monitoring PH+ CML after treatment
- hematologic tests: normal range of blood cell counts
- cytogenic tests: numbers of cells with PH+ chromosome
- molecular tests: q-RT-PCR: existence of PH+ DNA/mRNA
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nilotinib is cabable of
overcoming imatinib reisistance resulting from Brc-Abl kinase mutations
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Nilotinib clinical indication
chronic phase and accelerated phase PH+ CML resistant or intolerate to imatinib
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effectiveness of nilotinib is based on
hematologic and cytogenetic response rates
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do not use nilotinib is patients with
hypokalemia, long QT syndrome or hypomagnesemia.
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gemfitinib
EGFR
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erlotinib
EGFR
Tarceva
NSCLC, metastatic pancreatic cancer
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lapatinib
EGFR/Her2
Tykerb
breast cancer
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Afatinib
EGFR/Her2
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cigarette smoking decreases
erlotinib plasma concentrations
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severe ADRs of erlotinib
GI bleeding or perforations, renal disorders, hepatic disorders, ocular disorders- abnormal eyelash growth
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common ADRs of lapatinib
GI- diarrhea, dermatologic, fatigue
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severe ADRs of lapatinib
cardiac toxicity, hepatic toxicity, interstitial lung disease/pneumonitis
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multiple tyrosine kinases
sunitinib, sorafenib
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sunitinib
VEGFR, PDGFR, etc
Sutent
GIST, metastatic renal cell carcinoma
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sorafenib
mutiple tyrosine kinases/serine/threonine kinases
VEGFR, PDGFR, raf, etc
administer w/out food
Nexavar
hepatocellular carcinoma (HCC), renal cell carcinoma (RCC)
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sorafenib drug interactions
decetaxel, fluorouracil, gemcitabine, oxaliplatin, paclitaxel, doxorubicine, irinotecan
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sorafenib severe ADRs
wound healing complications
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interferones (IFNs)
are cytokines produced by the cells of the immune system in response to various challengers, particularly virus with double stranded RNA
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biological potency of IFNs are determined as
millium IU
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specific activity of IFN alfa-2b
2.6 X10^8 IU/mg protein
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potential MOA of IFN in tumor therapy (4)
- direct inhibition of cancer cell proliferation
- enhancement of cytotoxic T cell activities that kill cancer cells
- cell cycle regulation leading to tumor cells cytostasis and apoptosis
- increased expression of cell surface antigen/protein which facilitates immune cell recognition and cytotoxicity
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main site for catabolism of IFN?
kidney. No IFN in urine after administration
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;abeled indications for IFN therapy
PH+ CML, hairy cell leukemia, follicular lymphoma, AIDS-related kaposi's sarcoma, melanoma
18 yo and up
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IFN also has an unlabeled indiction for
renal cancer
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IFN drug interaction
may potentiate risk of renal failure in combo with IL-2
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acute ADRs of IFN
flu-like symptoms- fever, chills, HA
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chronic ADRs of IFN
depression, fatigue/weakness (most dose-limiting)
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incomplete Reiter's syndrom induced by
systemic IFN alpha
(tongue ulcers)
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do not use IFN-alpha with
autoimmune hepatitis (positive anti-nuclear antibody)
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interleukin-2
Proleukin
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biological potency of IL-2 is shown as
international units (IU)
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IL-2 receptor
1. requires binding to its IL-2 receptor
2. receptor belongs to class I cytokine receptor family
3. IL-2 receptor is composed of 3 units (alpha, beta and gammaC)
4. signaling is transmitted by members of JAK and STAT family
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IL-2 MOAs
1. enhancing lymphocyte mitogenesis and stimulation of long-term growth of IL-2-dependent cells
2. enhancing lymphocyte cytotoxicity
3. inducing lymphokine-activated (LAK) and NK activity
- pretty much increase number and function
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IL-2 rapidly distributes to
extravascular space
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IL-2 clinical indication
renal cell carcinoma, melanoma
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IL-2 injection should be reserved for patients with normal
cardiac and pulmonary function
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IL-2 and glucocorticoids
glucocorticoids reduce IL-2 induced side effects (Fever, renal insufficiency, hyperbilirubinemia, confusion and dyspnea) however, they also reduce the effectiveness and should be AVOIDED
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IL-2 has been associated with
- capillary-leak syndrome (CLS)
- impaired neutrophil function and increased risk of sepsis and bacterial endocarditis
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