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8/3/2019 Other Cancer Agents
1/22
VI. Other Agents
Indications: CML, Squamous cell
carcinoma of head and neck.
Off-label uses sickle cell disease,
thrombocytopenia, didanosine HIV
enhancement, refractory psoriasis
MOA: Interfers with DNA replication by
inhibiting ribonuceotide reductases and
inhibits thymidine incorporation
Capsules with rapid absorption, hepatic
metabolism and renal excretion, monitorfor any signs of bone marrow suppression
(leukopenia)
NH2
NH
OH
O
Hydroxyurea - Hydrea
8/3/2019 Other Cancer Agents
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Ribonucleotide Reductase
NH
N
N
O
NH2N
O
OH
HH
HHOH
OP-O
O
O-
NH
N
N
O
NH2N
O
H
HH
HHOH
OP-O
O
O-
NADPH + H+
Can you name another anticancer agent thatinterferes with this enzyme?
Gemcitabine HCl - Gemzar
Also Fludribine & Pentostatin
8/3/2019 Other Cancer Agents
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ClCl
CHCl2
Mitotane - Lysodren
Porfimer Sodium - Photofrin
Indication: Treatment of inoperable adrenal cortical carcinoma
MOA: adrenal cytotoxic agent that suppresses adrenalfunction and production of adrenal steroids both directly at theadrenal cortex and via peripheral metabolism of steroids
Discontinue use in cases of shock and severe trauma
Tablets, highly lipid soluble and can be detected for up to 10weeks, hepatic metabolism - use caution in impairment
Can cause brain damage and depression
Indications: Esophageal and endobronchial non-small cell lungcancer
Photodynamic therapyin which drug and laser light areadministered at the same time, tumor tissue harbors the agentselectively and for longer periods than normal tissue
MOA: porfimer is a photosensitizing agent that is injected into thetissue followed by 630 nm laser light generating oxygen freeradicals (singlet oxygen), superoxide and hydroxide radicalscausing tissue damage and tumor death
Last resort drug for palliative treatment
Other Agents
8/3/2019 Other Cancer Agents
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Enzymes - Asparaginase - Elspar and PEG-Asparaginase - Oncaspar
Asparaginase is produced by overexpression in Eschericia coliorErwinia carotovora accordingly it
is a foreign protein with high antigenicity
The immunogenicity of the protein is decreased by covalently binding polyethylene glycol to the
protein
Indications: Acute lymphocytic leukemia (ALL), Adult ALL, Chronic ALL
MOA: Asparginase is responsible for the hydrolysis of L-asparagine (a non-essential amino acid) to L-
aspartic acid ALL tumor cells lack L-asparagine synthase, the enzyme that produces L-asparagine
from L-aspartic acid and L-glutamine. So, ALL tumor cells can only get L-asparagine by diffusion from
the environment: PEG-asparaginase depletes L-asparagine from the tumor cell resulting in cytotoxicity
Some toxicity does occur to rapidly dividing normal cells that are dependent on exogenous L-asparagine,
Resistance arises due to tumor cells inducing production of asparagine synthetase so they can producetheir own L-asparagine
Half-life (t1/2) of PEG-modified enzyme and normal Asparaginase: PEG modified enzyme 2.6 to 7.1
days, Normal bacterial enzyme 0.6 to 1.2 days
Adverse reactions and contraindications too many to list
Drug interactions Note: Can decrease the effects of methotrexate (Rhumatrex),
Administration with vincristine (Oncovin) severe erythropoiesis disruption and neuropathy
Other Agents
8/3/2019 Other Cancer Agents
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CH3
CH3
CO2H
CH3
CH3CH3
Tretinoin - Vasanoid
CH2
CO2HCH
3CH3
CH3
CH3CH3
Bexarotene - Targretin
Indications: Induction of remission of acute promyelocyticleukemia containing the PML/RARa gene translocationgenetic defect
MOA: a non-cytolytic agent that induces maturation ofprimitive promyelocytes derived from the leukemic clonecell that decreases proliferation. Allows for repopulation of
normal periperal blood cells and hematopoietic cellsachieving complete remission
Retinoid toxicity: headache, fever, weakness, fatigue
Teratogenic USE contraception
Indications: Cutaneous T-cell lymphoma
MOA: binds retinoid receptors that function as transcriptionfactors that regulate genes thatpromote cellulardifferentiation and proliferation - inhibits growth andinduces tumor regression
Hepatic metabolism with heptobiliary excretion routesusecaution in hepatic impairment, Retinoid toxicity: headache,fever, weakness, fatigue
Teratogenic USE contraception
Other: Retinoids
8/3/2019 Other Cancer Agents
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Imatinib mesylate Gleevec
TM
Indications: chronic myeloid leukemia (CML) in blast crisis, accelerated phase
or in chronic phase after failure of interferon-alpha therapy
MOA: Tyrosine kinase inhibitor(TK controls cell growth and differentiation).
Induces apoptosis in CML cells that express an abnormal Bcr-Abl TK
Metabolism: hepatic CYP3A4 is the major CYP mode that demethylates the
drug followed by primarily fecal elimination
Drug interactions: CYP3A4 inhibitors increase plasma levels, imatinib is a
potent competitive inhibitor of CYP: 2C9, 2D6, 3A4,
Side effects: fluid retention and edema, GI irritation, neutropenia,
thrombocytopenia, hepatotoxicity (monitor liver enzymes), allergic reactions,
decreased urination
Supplied as 100 mg capsules (400 mg daily), contraindicated is breast feeding
N
N
N
N
N
NH
NHCH
3
O
CH3
CH3SO3H
Newer agents TKinhibitors
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Newer agents - TKinhibitors
Gefitinib Iressa (AstraZeneca)
Non Small Cell Lung Cancer (NSCLC) NSCLC expresses high levels ofepidermal growth factor receptor (EGFR) on
its cell surface EGFRis a surface receptor with a tyrosine kinase stimulate growth and
proliferation of cancer cells MOA unknown: believed tohave activity against EGFR tyrosine kinases Diarhea (48%), rash (43%), acne (25%), dry skin (13%), N&V (12%) Undergoes extensive hepatic metabolism primarily through CYP3A4: Many
drug interactions! Bleeding with warfarin!
250mg once daily. 30 pills = $1750
O
N O
MeO N
N
HN
F
Cl
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Monoclonal Antibody
8/3/2019 Other Cancer Agents
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8/3/2019 Other Cancer Agents
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Trastuzumab - Herceptin
Indication: Breast carcinoma
A recombinant DNA-derived humanized monoclonal antibody
specific for the HER2 protein located on the surface of metastatic
breast carcinomas
Metastatic tumors of the breast are large overexpressors of theHER2protein a transmembrane protein related to epidermal
growth factor
The term humanized means the antibody contains more human
protein sequence and is therefore less immunogenic in nature
Overexpressed/produced in Chinese hamster ovary cell cultures
Binding to the HER2 protein invokes antibody dependent
cell-mediated cytotoxicity via natural killer cells and
monocytes and prevents tumor cell proliferation
IV use only
Contraindication: Presence of Human Anti-Human antibody
Monoclonal Antibodies
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Rituximab - Rituxan
Indication: non-Hodgkins lymphoma (B-Cell Lymphomas)
Murine/tumor monoclonal antibody specific forCD20 antigen
located on the surface of B-cell precursor and mature B
lymphocytes: >90% of the B-cell non-Hodgkins lymphomas
CD20 regulates early activation process for cell cycle initiation and
differentiation, may actually be a calcium ion channel
The Fab portion of the antibody recruits immune functions that
mediate cell lysis or apoptosis, blocking CD20 prevents cell cycling
and differentiation
Overexpressed/produced in Chinese hamster ovary cell cultures IV use only
Contraindication: Presence of Human Anti-Human antibody or
Human Anti-Chimeric antibody
Drug interactions Patients taking antihypertensives should
discontinue use 12 hrs before infusion to prevent hypotension
Monoclonal Antibodies
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Gemtuzumab Ozogamicin- Mylotarg
Indication: acute myeloid leukemia (AML)
A murine/humanized monoclonal antibody covalently linked with
the cytotoxic antitumor antibiotic calicheamicin (isolated by Drew
Minnick from the fermentation goop of the bacterium
Micromonospora echinospora sp. calichensis)
Highly toxic agent severe anemias
MOA: Antibody portion binds selectively to the CD33 antigen
present on >80% of the human leukemias
The bound complex is taken into leukemia cells where
lysozyme releases the calicheamicin which binds to the minorgroove of DNA resulting in DNA double strand breaks and cell death
IV slow infusion only
Contraindication: Presence of Human Anti-Human antibody or
Human Anti-Chimeric antibody
Drug interactions unknown
Monoclonal Antibodies
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Immunostimulants
Alter host response to Cancer
Promotes non-malignant growth
Interferon E-2a (Roferon-A) &Interferon E-2b (Intron-A) Naturally occurring proteins (viral stimulus)
Recombinant DNA proteins
Enhance immune response to cancerAlter gene expression (keep cells dormant)
Best with hematologic cancers
I.M. or S.C. administration
Flu-like symptoms
8/3/2019 Other Cancer Agents
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Interleukin-2 is also known as T-cell growth factor
This compound results in the direct activation of cytotoxic T-lymphocytes and
natural killer cells - immunosurveillance to removed foreign, viral-infected and
cancer cells
Antagonists or antibodies to IL-2 may prove useful as immunosuppressiveagents for transplantation of organs
Products:
Aldesleukin - Proleukin
Non-glycosylated version of the natural IL-2 with several amino acid changes
Extremely toxic agentInteraction with the IL-2 receptor on immune cells leads to a cascade release of
many interferons, interleukins and tumor necrosis factor which leads to a proliferation
of B- and T-killer cells
Indications acute myelogenous leukemia, bone marrow transplant, HIV, leprosy,
malignant melanoma, non-Hodgkins lymphoma, renal cell carcinoma
IV or SC administration
Immunostimulants - Interleukins
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DenileukinDeftitox - Ontak
A cytotoxic fusion protein produced in an E. coliexpression system
Consists of the highly toxic fragments A and B of diphtheria toxin
covalently linked genetically to recombinant IL-2
Indications cutaneous T-cell lymphoma, mycosis fungoides, non-Hodgkins
lymphoma, psoriasis
Mechanism of action this toxin linked IL-2 analog is cytotoxic against cells that
express certain high-affinity IL-2 receptors containing a three protein complex
designated CD25/CD122/CD137. Upon binding to these receptors, the IL-2 toxin
complex is internalized by endocytosis. The A-fragment of diphtheria toxin is
cleaved and inhibits cellular protein synthesis leading to cell death in hours.
Accordingly, this drug is active against malignancies and cells that express the
high affinity IL-2 receptor.
Drug Interactions None known at this time---has no effect of Cytochrome P450
enzymes
Immunostimulants - Interleukins
8/3/2019 Other Cancer Agents
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N
SNH
HCl
Levamisole HCl - Ergamisol
Indications: adjunctive treatment along with 5-FU after surgical resections in
Dukes stage C colon cancer
MOA: Immunomodulator that restores depressed immune function by stimulating
antibody production, enhances T-cell responses, increases phagocytosis,
chemotaxis and mobility of neutrophils, macrophages and monocytes
Tablet dose form, extensively hepatically metabolized with renal excretion, monitorblood constituents and hepatic function---may cause agranulocytosis
Avoid alcohol use due to disulfiram like reaction
Notify MD of any flu-like symptoms or malaise
Immunostimulants
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BCG, intravesical (live, attenuated mycobacteria Bacillus of Clamette
and Guerin strain ofMycobacterium bovis) Pacis, TICE BCG,
TheraCys
Indications: Carcinoma in situ in the urinary bladder with papillary tumors
Caution: health care workers have been infected due to needle sticks and lacerations
treat this material as a biohazardous agent with respect to handling and disposal
MOA: Intravesical delivery in the bladder results in infection that promotes local acute
inflammatory responses and sub-acute granulomatous reaction with macrophage and
lymphocyte infiltration: results in a T-lymphocyte based anti-tumor activity
If a cough develops contact MD immediately due to systemic BCG infection; notify MD ofany increase in normal symptoms of the patients disease
Do not use in UTI, feverclosely monitor for infections
Always void while in the seated position (no standing guys) into undiluted bleach to
prevent spreading the organisms to other people
Immunostimulants
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Angiogenesis Inhibitors
Promising Research Area
Fights primary tumor only!
Decrease tumor growth
Inhibit new blood vessel growth angiopoietin-1
basic fibroblast growth factor (bFGF)
vascular endothelial growth factor (VEGF).
Angiostatin - protein Binds ATP synthase receptors
Inhibits metasteses (mice)
Endostatin - protein Causes primary tumor regression (mice)
8/3/2019 Other Cancer Agents
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1. Chromic Phosphate (32P) - Phosphocol P32
Indications: intracavity injection for treatment of peritoneal or pleural effusions in
metastatic cancer, also interstitial injection, NOT for IV use
MOA: F-particle radiation emission with a t1/2 of 14.3 days
Side effects transitory radiation sickness, N/V, bone marrow depression
2. Sodium iodide (131I) - IodotopeIndications: Selected cases of thyroid cancer (only certain cell types will take up) or
treatment of hyperthyroidism
MOA: oral use 90%F-particle and 10% K-particle radiation emission with a t1/2 of
8 days - kidney excreted
Drug uptake is decreased by recent iodine ingestion or via contrast agents
Side effects transitory radiation sickness - N/V, temporary hair thinning, sore
throat, cough, hematological depression possiblewatch for infectionsMay take up to three months for positive results to appear in treatment of
hyperthyroidism
3. Sodium phosphate (32P) - genericsIndications: Leukemias and skeletal metastatic disease
MOA: injection only F-particle radiation emission with a t1/2 of 14.3 days
Side effects transitory radiation sickness - hematological depression possiblewatch for infections
Radiopharmaceuticals
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4. Strontium-89 Chloride - Metastron
Indications: painful skeletal metastatic disease
IV injection only
MOA: pure F-particle radiation emission with a t1/2 of 50.5 days
2/3 excreted in the urine and 1/3 fecal excretion with bone turnover rate of every 14
days---use caution in renal failure
Side effects transitory radiation sickness, N/V, bone marrow depression
Bone pain worst first 2-3 days following therapy - increase pain meds
Use a normal toilet (not a urinal) to prevent spread of radiation the first week
5. Samarium Lexidronam (153Sm) - Quadramet
Indications: painful skeletal metastatic disease confirmed by bone scans,
rheumatoid arthritis, ankylosing spondylitis
IV injection only
MOA: F-particle radiation emission (640-810 keV) and K-particle radiation emission
Renally excreted within 24 hours
Side effects transitory radiation sickness, N/V, bone marrow depression
Use a normal toilet to prevent spread (12 hours), store contaminated clothing for
several weeks radiation decay
Always verify dosage before giving any of these agents to a patient
Radiopharmaceuticals
8/3/2019 Other Cancer Agents
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Brachytherapy radioactive implants
The implants or seeds are tiny, sealed capsules that contain precise dosages of a
radioactive element
Typically 60-100 seeds are implanted into the cancerous tissue in a procedurecalled interstitial brachytherapy
Trade name is PharmaSeed sold by Syncor International Corporation
Contain either Iodine-125 or Palladium-103
Indicated for prostate cancer therapy
Radiopharmaceuticals
8/3/2019 Other Cancer Agents
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Indium-111 or Yttrium-90 radiolabled Ibritumomab Tiuxetan Zevalin First (approved March 26, 2002) Smart bomb approach to targeting radiation
directly to cancer cells
The first radioimmunotherapy drug which is a 3 part immunoconjugate
consisting of 3 parts1. Ibritumomab (a murine IgG1 kappa monoclonal antibody targeted against the antigenCD20 present on the surface of normal and malignant B lymphocytes)
2. The antibody is coupled via a stable thiourea covalent bond to the linker-chelator
group called Tiuxetan
3. The radioisotope 111In (electron capture decay producing a gamma ray 2.81 day
half-life) or90Y (Beta particles 5 mm distance 2.67 day half-life)
Indications: Resistant or recurrent form of non-Hodgkin lymphoma called low-grade orfollicular lymphoma: Two treatment shots: a test shot to see if the lymphoma is
responsive and one week later a real dose
Toxicity possible: Infection due to loss of white cells and platelets requiring transfusionsand a possible first dose fatal infusion reaction (80% of the patients) hypoxia,
pulmonary infiltrates - ARDS, MI, cardiogenic shock - the antibody portion is
produced in Chinese hamster ovary cells
Radiopharmaceuticals