VI. Other Agents

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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, monitor
for any signs of bone marrow suppression
(leukopenia)
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Ribonucleotide Reductase
NADPH H
Can you name another anticancer agent that
interferes with this enzyme?
Gemcitabine HCl - Gemzar
Also Fludribine Pentostatin
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Other Agents
Indication Treatment of inoperable adrenal
cortical carcinoma MOA adrenal cytotoxic agent
that suppresses adrenal function and production
of adrenal steroids both directly at the adrenal
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 10 weeks, hepatic
metabolism - use caution in impairment Can cause
brain damage and depression Indications
Esophageal and endobronchial non-small cell lung
cancer Photodynamic therapy in which drug and
laser light are administered at the same time,
tumor tissue harbors the agent selectively and
for longer periods than normal tissue MOA
porfimer is a photosensitizing agent that is
injected into the tissue followed by 630 nm laser
light generating oxygen free radicals (singlet
oxygen), superoxide and hydroxide radicals
causing tissue damage and tumor death Last resort
drug for palliative treatment
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Other Agents

• Enzymes - Asparaginase - Elspar and
  PEG-Asparaginase - Oncaspar
• Asparaginase is produced by overexpression in
  Eschericia coli or Erwinia 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 produce their 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

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Other Retinoids
Indications Induction of remission of acute
promyelocytic leukemia containing the PML/RARa
gene translocation genetic defect MOA a
non-cytolytic agent that induces maturation of
primitive promyelocytes derived from the leukemic
clone cell that decreases proliferation. Allows
for repopulation of normal periperal blood cells
and hematopoietic cells achieving complete
remission Retinoid toxicity headache, fever,
weakness, fatigue Teratogenic USE
contraception Indications Cutaneous T-cell
lymphoma MOA binds retinoid receptors that
function as transcription factors that regulate
genes that promote cellular differentiation and
proliferation - inhibits growth and induces tumor
regression Hepatic metabolism with heptobiliary
excretion routesuse caution in hepatic
impairment, Retinoid toxicity headache, fever,
weakness, fatigue Teratogenic USE
contraception
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Newer agents TK inhibitors

• Imatinib mesylate GleevecTM
• 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

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Newer agents - TK inhibitors

• Gefitinib Iressa (AstraZeneca)
• Non Small Cell Lung Cancer (NSCLC)
• NSCLC expresses high levels of epidermal growth
  factor receptor (EGFR) on its cell surface
• EGFR is a surface receptor with a tyrosine kinase
  ? stimulate growth and proliferation of cancer
  cells
• MOA unknown believed to have activity against
  EGFR tyrosine kinases
• Diarhea (48), rash (43), acne (25), dry skin
  (13), NV (12)
• Undergoes extensive hepatic metabolism primarily
  through CYP3A4 Many drug interactions!
• Bleeding with warfarin!
• 250mg once daily. 30 pills 1750

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Monoclonal Antibody
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Monoclonal Antibodies

• 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 the HER2 protein 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

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Monoclonal Antibodies

• Rituximab - Rituxan
• Indication non-Hodgkins lymphoma (B-Cell
  Lymphomas)
• Murine/tumor monoclonal antibody specific for
  CD20 antigen located on the surface of B-cell
  precursor and mature B lymphocytes gt90 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

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Monoclonal Antibodies

• 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 gt80 of the human
  leukemias
• The bound complex is taken into leukemia cells
  where lysozyme releases the calicheamicin which
  binds to the minor groove 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

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Immunostimulants

• Alter host response to Cancer
• Promotes non-malignant growth
• Interferon a-2a (Roferon-A) Interferon a-2b
  (Intron-A)
• Naturally occurring proteins (viral stimulus)
• Recombinant DNA proteins
• Enhance immune response to cancer
• Alter gene expression (keep cells dormant)
• Best with hematologic cancers
• I.M. or S.C. administration
• Flu-like symptoms

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Immunostimulants - Interleukins

• 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 immunosuppressive agents for
  transplantation of organs
• Products
• Aldesleukin - Proleukin
• Non-glycosylated version of the natural IL-2 with
  several amino acid changes
• Extremely toxic agent
• Interaction 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

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Immunostimulants - Interleukins

• Denileukin Deftitox - Ontak
• A cytotoxic fusion protein produced in an E. coli
  expression 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

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Immunostimulants
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, monitor blood constituents
and hepatic function---may cause
agranulocytosis Avoid alcohol use due to
disulfiram like reaction Notify MD of any
flu-like symptoms or malaise
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Immunostimulants
BCG, intravesical (live, attenuated mycobacteria
Bacillus of Clamette and Guerin strain of
Mycobacterium 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 of any 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
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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)

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Radiopharmaceuticals

• 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 b-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) - Iodotope
• Indications Selected cases of thyroid cancer
  (only certain cell types will take up) or
  treatment of hyperthyroidism
• MOA oral use 90 b-particle and 10
  g-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
  infections
• May take up to three months for positive results
  to appear in treatment of hyperthyroidism
• 3. Sodium phosphate (32P) - generics
• Indications Leukemias and skeletal metastatic
  disease
• MOA injection only b-particle radiation
  emission with a t1/2 of 14.3 days
• Side effects transitory radiation sickness -
  hematological depression possiblewatch for
  infections

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Radiopharmaceuticals

• 4. Strontium-89 Chloride - Metastron
• Indications painful skeletal metastatic disease
• IV injection only
• MOA pure b-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 b-particle radiation emission (640-810 keV)
  and g-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

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Radiopharmaceuticals

• 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 procedure called
  interstitial brachytherapy
• Trade name is PharmaSeed sold by Syncor
  International Corporation
• Contain either Iodine-125 or Palladium-103
• Indicated for prostate cancer therapy

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Radiopharmaceuticals

• 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 parts
• Ibritumomab (a murine IgG1 kappa monoclonal
  antibody targeted against the antigen CD20
  present on the surface of normal and malignant B
  lymphocytes)
• The antibody is coupled via a stable thiourea
  covalent bond to the linker-chelator group called
  Tiuxetan
• The radioisotope 111In (electron capture decay
  producing a gamma ray 2.81 day half-life) or
  90Y (Beta particles 5 mm distance 2.67 day
  half-life)
• Indications Resistant or recurrent form of
  non-Hodgkin lymphoma called low-grade or
  follicular 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 transfusions
  and 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