VI.

Other Agents
O H2N N H OH
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)

Hydroxyurea - Hydrea

Ribonucleotide Reductase

NH

N NH

O -O P O
-

NH2

NH2

O H H OH

NADPH + H+
O H H OH

-O

P O-

O H H OH

O H H H

Can you name another anticancer agent that interferes with this enzyme?

Gemcitabine HCl - Gemzar

Also Fludribine & Pentostatin

Other Agents
Indication: Treatment of inoperable adrenal cortical carcinoma
CHCl2

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
Cl

Cl

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

Mitotane - Lysodren

Porfimer Sodium - Photofrin

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 Laspartic 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

Other: Retinoids
H3 C CH3 CH3 CH3 CO2H

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

CH3

Tretinoin - Vasanoid

H 3C

CH3

CH2

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

H 3C

CH3

CH3

CO2H

Bexarotene -

Targretin

Newer agents
N N

TK inhibitors
H N CH3 N HN N O CH3SO3H CH3

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

Newer agents - TK inhibitors

F O N O N HN Cl

MeO

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%), N&V (12%) Undergoes extensive hepatic metabolism primarily through CYP3A4: Many drug interactions!


Bleeding with warfarin!

250mg once daily. 30 pills = $1750

Monoclonal Antibody

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

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: >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
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 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

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 cancer Alter gene expression (keep cells dormant) Best with hematologic cancers I.M. or S.C. administration Flu-like symptoms

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

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

Immunostimulants
H N N S 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, 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

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

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) Causes primary tumor regression (mice)

Endostatin - protein


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: 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) - Iodotope Indications: 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 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 F-particle radiation emission with a t1/2 of 14.3 days Side effects transitory radiation sickness - hematological depression possible watch for infections

Radiopharmaceuticals
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
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

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
1. 2. 3. 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