Other Cancer Agents

8/3/2019 Other Cancer 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, monitorfor any signs of bone marrow suppression

(leukopenia)

NH2

NH

OH

O

Hydroxyurea - Hydrea


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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


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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


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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


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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


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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


9/22


10/22

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



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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



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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


14/22

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


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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


17/22

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)


19/22

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


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


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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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



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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


Other Cancer Agents

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