review of chemotherapy pharmacology - khon kaen … inc. item and derived items©2010 by saunders,...
TRANSCRIPT
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REVIEW OF CHEMOTHERAPY
PHARMACOLOGY
Suphat Subongkot, Pharm.D, BCPS, BCOP
Clinical Pharmacy, Khon Kaen University, Thailand
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Learning Objectives
1. Identify the mechanism of action of the major classes of chemotherapy and targeted agents.
2. Apply the dose modifications for antineoplastics in patients with renal and hepatic dysfunction.
3. Summarize the mechanisms of resistance associated with antineoplastics and targeted agents. Describe the strategies utilized to overcome these resistance mechanisms.
4. List the dose limiting toxicities as well as any unique toxicities of each antineoplastic agent or targeted agent.
5. Summarize the tumor growth hypotheses that have been used to model cancer cell death from antineoplastic therapy.
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Which of the following regarding
chemotherapy and the cell cycle are correct?
A. Cisplatinisnon-cellphase specific and works best
on resting cells
B. Topotecan would be best administered as a
continuous infusion or on multiple days
C. Docetaxel’s MOA is in the early part of the M
phase of the cell
D. Alkyaling agents are cell- phase specific agents
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DNA is Information
DNA
A, T, G, C
Codon
Gene
Chromosome
Genome
ENGLISH
A to Z
Word
Sentence
Chapter
Book
4
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5
Elsevier inc. item and derived items©2010 by saunders, an imprint of Elseveir Inc.
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Cell Cycle
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Principles of Chemotherapy:
Action Sites of Cytotoxic Agents
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Non-Cell Phase Specific Agents
Exert their cytotoxic effect throughout the cell
cycle
Cell kill is proportional to dose
Alkylating agents
Nitrogen mustards, cyclophosphamide, cisplatin,
carboplatin
Antitumor antibiotics
Doxorubicin, daunorubicin
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Cell Phase Specific Agents
Toxic to the proportion of cells in the part of the cell cycle in which the agent is active.
Antimetabolites
Antifolates: Methotrexate
Pyrimidine antagonists
Purine analogs
Plant Alkaloids
Vinca alkaloids
Epipodophyllotoxins
Camptothecins
Paclitaxel
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Optimizing dosing schedules
10
Elsevier inc. item and derived items©2010 by saunders, an imprint of Elseveir Inc.
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Tumor growth kinetics 11
Chemotherapy of benefit
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The HER Family and Ligands
Yarden Y, et al. Nat Rev Mol Cell Biol. 2001;2:127-137.
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Activated EGFR-TK: A Pivotal Driver
of Malignancy
P = phosphate group.
Harari PM, et al. Clin Cancer Res. 2000;6:323-325; Herbst RS. Int J Radiat Oncol Biol Phys. 2004;59(2 suppl):21-26
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Alkylating Agents
Nitrogen mustards
Chlorambucil, Cyclophosphamide, Ifosfamide, Melphalan,
Mechlorethamine hydrochloride, bendamustine
Nitrosoureas
Carmustine, Lomustine, Semustine, Streptozocin
Alkyl sulfonates
Busulfan
Ethylenimines
Thiotepa, Hexamethylmelamine
Triazenes
Dacarbazine
Platinum analogues
Cisplatin, Carboplatin, Oxaliplatin
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Alkylating Agents MOA
ethylene immonium ion
15
Goodman and gilman's the pharmacological basis of therapeutics, 11 Edition.
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Alkylating Agents MOA
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Alkylating Agents MOA
Adapted from. Goodman and gilman's the pharmacological basis of
therapeutics, 11 Edition: http://www.accesspharmacy.com
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Additional Alkylators
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Which of the following agents produce the greatest
inhibition of myelocytic bone marrow cell proliferation ?
A. Cyclophosphamide
B. Carboplatin
C. Docetaxel
D. Busulfan
E. All of the aboveare equally toxic
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Metabolic Pathway of Alkylators`
Sterrns V, et al. Nat Rev Cancer. 2006;6:886-93.
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Temozolomide vs. Dacarbazine
Stearns V, et al. Nat Rev Cancer. 2006;6:886-93.
ACCP/ASHP Oncology Pharmacy Preparatory Review Course
Temozolomide vs. Dacarbazine
Stupp R, et al. Lancet Oncol. 2001;2:552-60.
ACCP/ASHP Oncology Pharmacy Preparatory Review Course
Platinum Analogues
Cisplatin Carboplatin
Oxaliplatin
Stupp R, et al. Lancet Oncol. 2001;2:552-60.
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Platinum Analogues
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Platinum Crosslinks
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Clinical differences
Cisplatin Carboplatin
Myelosuppression / //
Nephrotoxicity // x
Otototoxic / x
Neuropathy / x
Emetogenicity //// //
24
J Clin Oncol 2012;30:1692-8.
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Which drug inhibits DNA topoisomerase II and
causes DNA breakdown?
A. Methotrexate
B. Paclitaxel
C. Topotecan
D. Epirubicin
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Molecular Function of Topoisomerase
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Topoisomerase II inhibitors prevent the
rejoining DNA 27
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Anthracyclines
MOA
Inhibits topoisomerase II.
This prevents the religation of DNA during DNA replication
causing DNA strand breaks.
Dose reductions required in patients with hepatic
impairment.
Decrease dose
by 50% if bilirubin levels 1.2-3.0 mg/dL and
by 75% for bilirubin > 3.0 mg/dL;
generally omitted if bilirubin > 5.0 mg/dL.
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Dosage Adjustment of Hepatic Impairment
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Dosage Adjustment of Hepatic
Impairment
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Anthracyclines
Toxicities
Potent vesicants. Apply cold ice pack and evaluate for antidote
use (99% DMSO 1-2 ml applied to site every 6 hours for 7-14
days) or Totect®.
Dose limiting myelosuppression (primarily leukopenia), chronic
cardiomyopathies. All patients should have a baseline MUGA
done to evaluate potential cardiotoxicity.
Additional toxicities include:
dose dependent nausea and vomiting, alopecia, and radiation recall.
Turns urine red, need to counsel patients on this AE.
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Anthracyclines
Sites of Difference in activites
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Etoposide (VP-16)
MOA: Topoisomerase II inhibitor
Dosage and Administration:
50 to 200mg/m2/day IV for 3-5 days every 3 weeks
IV infusion should be infused over 30-60 minutes to avoid
hypotension
Oral dose is 2x greater than the IV
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Etoposide (VP-16)
Toxicities:
Dose limiting myelosuppression
primarily leukopenia.
Additional toxicities include
nausea and vomiting (with oral dosing),
alopecia
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Topo I Inhibitors Mechanism of Action
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Antimicrotubules
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Vinca Alkaloids
Dose reductions required in patients with hepatic
impairment.
Decrease dose
by 50% if bilirubin levels 1.5-3.0 mg/dL and
by 75% for bilirubin > 3.0 mg/dL;
generally omitted if bilirubin > 5.0 mg/dL.
Toxicities
All vinca alkaloids are potent vesicants,
apply warm pack and administer hyaluronidase
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Vinca Alkaloids
Vinblastine Vincristine
• Dose limiting leukopenia,
and thrombocytopenia.
• Additional toxicities
include: Neurologic toxicity,
constipation, abdominal
cramps (much less than
vincristine)
• Dose-limiting neurologic
toxicity, constipation, and
paralytic ileus.
• Rarely causes bone marrow
suppression and SIADH
• In general, the maximum
dose of vincristine is 2mg
weekly
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Paclitaxel & Docetaxel
Paclitaxel
Dose limiting leukopenia
Additional toxicities include: Hypersensitivity reactions,
alopecia, cardiac
Toxicity, peripheral neuropathies, and mucositis
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Paclitaxel & Docetaxel
Docetaxel
Dose limiting leukopenia
Additional toxicities include:
Peripheral edema, alopecia, peripheral
Neuropathies, and hypersensitivity reactions.
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Paclitaxel & Docetaxel
Miscellaneous:
Patients must receive premedication prior to
receiving paclitaxel to decrease the incidence of
hypersensitivity reactions
Patients receive both pre and postmedication with
docetaxel to prevent the fluid retention associated
with use
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Epothilones:
Thiazole side-chain
occupies the region of
binding site not
occupied by taxanes
Only 1 polar contact
point (C7-OH) is
shared with taxanes
EpoA and paclitaxel bound to beta-tubulin
Specifically and Uniquely Bind to Beta-Tubulin
Nettles et al. Science. 2004;305:866-869.
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Epothilone Differences Versus Taxanes
5-25 times more potent than paclitaxel in vitro
Efficacy not impaired by Pg-protein expression
Potential benefit with altered B-tubulin binding
Paclitaxel resistant Ala to Thr substitution at residue
364 sensitive to Epo
Epothilone resistance associated with substitutions at
residues 274 or 282, as well as high class III B-tubulin
expression
Goodin, S. et al. J Clin Oncol 2004;22:2015-25 Verrills, NM., et al. Chem Biol 2003;10:597-607
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Eribulin
Synthetic analog of the marine macrolide
halichondrin B that inhibits tubulin polymerization
Inhibits growth (but not shortening of microtubules)
Approved for metastatic breast cancer after two
agents (including taxane and anthracycline)
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Eribulin
Adverse effects appear to similar to vinblastine
(neutropenia), with a decreased incidence of
neuropathy compared to vincristine
Requires dose adjustments based on hepatic and
renal function
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Dosage adjustment in Renal impairment
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Dosage adjustment in Renal impairment
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Antimetabolites
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Purine and Pyrimidine analogues
Need purine bases—A, G
Need pyrimidine bases—C, T (DNA) and C, U (RNA)
Can build in two ways— de novo and salvage
pathways
All cells use both
Continuously dividing cancer cells favor de novo
synthesis
many drugs are directed here in an attempt to provide
selectivity over normal cells
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Purine Analogues
Mercaptopurine and thioguanine
These analogues are converted in the body to the
ribonucleotide form, which incorporate in the DNA to
prevent purine synthesis.
Fludarabine (2-fluoro-ara-AMP):
The triphosphate form inhibits ribonucleotide reductase
and DNA polymerase.
Pentostatin (2’-deoxycoformycin) and cladrabine
Inhibits ribonucleotide reductase
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Purine Analogues
Increase risk of infection
Bacteria (Listeria, Staph, Strep)
Fungal (Candida, Aspergillus, Cryptococcus)
Viral (Herpes Zoster, Varicella, CMV)
Other (Pneumocystis carinii)
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Metabolism of thiopurine
Myelosuppression
52
Exp Rev Gastroenterol Hepatol 2010;4:575-88.
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Genotype-Guided 6-MP Dosing
Standard dose
Heterozygous
60% of standard dose
Homozygous
10% of standard dose
53
Pharmacogenomics 2002;3:89-98.
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Dose adjustment:
High TPMT (> 65 U/mL): dose
Intermediate TPMT (25-45 U/mL): dose 20-50%
Low or absence TPMT (< 25 U/mL): dose 80-90%
Phenotype-Guided 6-MP Dosing
54
Annals of Internal Medicine 2011;154:814-823.
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Pyrimidine Analogues
Gemcitabine and cytarabine
Triphosphorylated to active drug which inhibits DNA
polymerase
5-FU and capecitabine
Inhibit thymidylate synthase
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56
Cytarabine (Ara-C)
Ara-C
Ara-U
Ara-UMP
Ara-CTP
Ara-CDP
Ara-CMP
Cytidine deaminase
dCMP deaminase
NDP kinase
dCMP kinase
Deoxycytidine kinase
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Metabolism of Azacitidine and
Decitabine
Baylin SB, et al. Nat Clin Pract Oncol. 2005; 2: S4–S11 doi:10.1038/ncponc0354
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Methotrexate
Mechanism
Inhibits DHFR that prevents the conversion of dihydrofolate (FH2) to tetrahydrofolate (FH4)
Toxicities
Dose limiting leukopenia and thrombocytopenia.
Renal tubular necrosis seen with high dose therapy.
Vigorous hydration and alkylation of the urine necessary to decrease risk of kidney damage.
Additional toxicities include:
Pulmonary pneumonitis, alopecia, and stomatitis and mucositis.
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Methotrexate
High dose therapy (500-12,000 mg/m2) require
leucovorin rescue until MTX levels are less than
0.05 M (5 x 10-8 M)
Provides a source of reduced folate
Does not protect against renal toxicity (need
bicarbonate)
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60
Leucovorin
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Leucovoring Recue Nomogram
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Administration
62
Oncologist 2006;11:694-703..
24 48 72
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63
Glucarpidase(carboxypeptidaseG2)
Therapeutics and Clinical Risk Management 2012:8 403–413
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Pemetrexed MOA
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Tamoxifen
Mechanism Of Action: Anti-estrogen (in breast) that
inhibits nuclear binding of the estrogen receptor,
blocking estrogen stimulation of breast cancer cells.
Indication: Tamoxifen main use is in the treatment of
estrogen- receptor positive breast cancer.
Also approved for the prevention of breast cancer
in women deemed to be at high risk
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Tamoxifen
Toxicities:
Menopausal symptoms: Hot flashes, nausea, and
vomiting. Additional toxicities include vaginal bleeding,
bone pain, menstrual irregularities, headache, and
depression.
Rare toxicities include retinal toxicity and
thromboembolic disorders. Concomitant warfarin
therapy may increase your risk of bleeding.
The risk of endometrial is approximately 3x the normal
population.
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Selective Versus Nonselective
Aromatase Inhibition
Federman, DD: The Adrenal. Dale DC, Federman DD, eds. In: Scientific American Medicine. Section 3. Subsection IV.
©1997 Scientific American Inc. All rights reserved.
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Strategies for Therapeutically
Targeting the Androgen Receptor
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What are Targeted Therapies?
Therapies directed towards a specific target on cells
that affects angiogenesis and cell cycle mechanisms
Main targets:
Cell specific markers
EGFR- Epidermal Growth Factor Receptor
VEGF- Vascular Endothelial Growth Factor
Therapies
Monoclonal Antibodies
Tyrosine Kinase Inhibitors
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Antibody Structure
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Mechanism of Action of Antibody
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Nomenclature
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Which of the following monoclonal antibodies would be
expected to cause the lowest incidence of human-
antimouse antibodies (HAMA) reactions ?
A. Epratuzumab
B. Cetuximab
C. Bevacizumab
D. Panitumumab
E. Tositumomab
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Monoclonal Antibodies
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Ofatumumab
• Human CD20 mAb Binds
a small-loop epitope of
CD20
• Effective CDC of cells
with low CD20
expression, including
CLL cells
• More effective in vitro
CDC versus rituximab
Cheson BD. J Clin Oncol 2010;28:3525-2530.
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Brentuximab Vedotin: Mechanism of
Action
An antibody drug
conjugate directed
against the CD30
antigen on
Hodgkin’s cells
Katz J, et al. Clin Cancer Res.
2011;17:6428-6436.
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Biological Activities of CTLA-4
Antibody Blockade
Mellman I, et al. Nature. 2001;480:480-489.
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The HER Family and Ligands
Yarden Y, et al. Nat Rev Mol Cell Biol. 2001;2:127-137.
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Which of the following statements about
tyrosine kinase inhibitors is true?
A. They are usually administered via intravenous
infusion due to their molecular size.
B. They compete with a natural ligand for binding to
their target receptor.
C. They work intracellulary and prevent signal
transduction after the receptor has been activated.
D. They work intracellulary to prevent the
dimerization of growth factor receptors
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Anti-HER Blocking Monoclonal Antibodies
Moyer JD, et al. Cancer Res. 1997;57:4838-4848.
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Mutational Status and EGFR Response
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TKIs
Drug Target MOA
Trastuzumab Her-2 extracellular
receptor •Decrease in cell
proliferation
• Induce apoptosis
•Decrease angiogenesisCetuximab and
panitumumab
Her-1 [EGFR]
extracellular receptor
Erlotinib and gefitinib Her-1 [EGFR] tyrosine
kinase
Lapatinib Her-1 [EGFR] and Her-2 tyrosine
Kinase•As above but has activity
after trastuzumab relapse
ACCP/ASHP Oncology Pharmacy Preparatory Review Course
ARS Question # 6
Which best explains sunitinib’s mechanism of
action?A. Inhibits the tyrosine kinase activity of
multiple receptors, such as VEGFR and
PDGFR, involved in tumor growth and
angiogenesis.
B. Competitive inhibitor of the VEGFR
and PDGFR extracellular receptors
involved in angiogenesis.
C. Competitive inhibitor of the EGFR and
Her-2 receptor involved in tumor
growth.
D. Inhibits the EGFR tyrosine kinase
activity involved in tumor growth and
angiogenesis.
ACCP/ASHP Oncology Pharmacy Preparatory Review Course
Rini BI, et al. Clin Cancer Res. 2007;13:1098-1106
Mechanism of Action of Current VEGF Inhibitors
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Which best explains sunitinib’s mechanism of
action?
A. Inhibits the tyrosine kinase activity of multiple
receptors, such as VEGFR and PDGFR, involved in
tumor growth and angiogenesis.
B. Competitive inhibitor of the VEGFR and PDGFR
extracellular receptors involved in angiogenesis.
C. Competitive inhibitor of the EGFR and Her-2
receptor involved in tumor growth.
D. Inhibits the EGFR tyrosine kinase activity involved
in tumor growth and angiogenesis.
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Mechanism of Action of Current
VEGF Inhibitors
Rini BI, et al. Clin Cancer Res. 2007;13:1098-1106
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Vendetanib
Mechanism Of Action: Small-molecule inhibitor of
vascular endothelial growth factor receptor
(VEGFR), epidermal growth factor receptor (EGFR),
and RET tyrosine kinases
Mutations in RET proto-oncogene seen in the
majority of medullary thyroid cancers
300 mg PO daily with or without food (decrease to
200 mg in patients with CrCl < 50ml/min); avoid in
Childs-Pugh B or C Toxicities
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Vendetanib
Black box-QTc prolongation (Monitor EKG at
baseline; 2 to 4 weeks and 8 to 12 weeks after
starting; and every 3 months thereafter). Avoid in
patients with hypocalcemia, hypokalemia, or
hypomagnesemia
CYP 3A4 substrate
Langmuir PB, et al. Clin Pharmacol Ther. 2012;91:71-80.
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Imatinib
Indications:
Initial or salvage therapy for CML
Treatment of patients with Kit (CD117) positive
unresectable and/or metastatic malignant
gastrointestinal stromal tumors (GIST)
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Imatinib
Mechanism
Inhibits the tyrosine kinase activity of Bcr-Abl
Inhibits c-Kit and platelet-derived growth factor
receptor
Place in therapy: CML, GIST
Inhibitor and substrate of CYP3A4
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Newer bcr-abl Inhibitors
Dasatinib
Inhibits the following kinases: BCR-ABL, SRC family
(SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ
Binds to inactive and active comformations
70 mg PO BID or 140 mg QD
CYP3A4 Inhibitor
Myelosuppression and pleural effusions are DLT
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Newer bcr-abl Inhibitors
Nilotinib
MOA similar to imatinib but binds to BCR-ABL 20-50
times more potent
Like imatinib binds to inactive bcr-abl conformations
Kantarjian HM, et. al. Ann Intern Med. 2006;145:913-923
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A Simplified Illustration of BCR-ABL and Src Family
Kinase Involvement in Oncogenic Signaling Pathways
Kantarjian HM, et. al. Ann Intern Med. 2006;145:913-923.
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Proteasome Inhibition by Bortezomib
Armand JP, et al. Oncologist. 2007;12:281-290
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mTOR Inhibitor Mechanism of Action
Brugarolas J. N Engl J Med. 2007;356:185-187
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Crizotinib
Inhibits multiple receptor tyrosine kinases
Anaplastic lymphoma kinase (ALK)
Hepatocyte growth factor receptor (HGFR, c- Met)
Recepteur d’Origine Nantais (RON)
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Crizotinib
Approved for locally advanced or metastatic
NSCLC that is ALK-positive
Companion diagnostic test designed to detect
rearrangements of the ALK gene
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ALK Fusion Oncogenes and
Downstream Signaling Pathway
haw AT, et al. Clin Cancer Res 2011;17:2081-2086.
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Vemurafenib
BRAF kinase inhibitor
Inhibits kinase activity of certain mutated forms of
BRAF, including BRAF with V600E mutation (present
in ~50% of melanomas)
Not active against cells with wild-type BRAF
Dose
960 mg orally twice daily until disease progression
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Activated EGFR-TK: A Pivotal Driver
of Malignancy
P = phosphate group.
Harari PM, et al. Clin Cancer Res. 2000;6:323-325; Herbst RS. Int J Radiat Oncol Biol Phys. 2004;59(2 suppl):21-26
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Vorinostat Mechanism of Action
Causes the accumulation of acetylated histones and induces cell cycle arrest
and/or apoptosis of cancer cells.
Kavanaugh SM, et al. Am J Health Syst Pharm. 2010;67:793-7.
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In which of the following cases would you either not
dispense the chemotherapy or adjust the dose
appropriately?
A. Daunorubicin-MUGA of 52%
B. Bendamustine-Bilirubin of 2.2mg/dL
C. Vinorelbine-CrCl of 32ml/min
D. Doxorubicin-Bilirubin of 1.9mg/dL
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THANK YOU FOR YOUR ATTENTION