Monoclonal Ab & Tyr Kinase Inhibitors
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Transcript of Monoclonal Ab & Tyr Kinase Inhibitors
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Monoclonal Antibodies:
Used In Cancer Chemotherapy
USA FDA Approved Antibodies For Treatment Of Cancer:
Classification:
Unconjugated Mabs: Origin Isotype Indication Target
Rituximab: Rituxan Chimeric Human Ig1 NHL CD20
Trastuzumab:Herceptin Humanized Human Ig1 Breast Cancer HER-2
Alemtuzumab: Campath Humanized Human Ig1 CLL, CD-52
NHL,Promyelocytic
Leukemias
Cetuximab: Erbitux Chimeric Human Ig1 Colorectal, EGFR
Head &Neck
Cancer
Bevacizumab: Avastin Humanized Human Ig1 Colorectal & VEGF
Lung Cancer
Panitumumab: Vectibix Human Human Ig2 Colorectal EGFR
Xeno-Mouse Cancer
Immunoconjuates:
Gemtuzumab (Mylotarg) Humanized HumanIg4 AML CD33
(Calicheamicin
Conjugate )
Ibritumomab( Zevalin) Murine Murine Ig G1 NHL CD20
(90Y-Comjugate)
Tositumomab( Bexxar) Murine Murine IgG2A NHL CD20
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Mechanisms: Target Drug
1. Ligand Sequestrating/ VEGF-A Bevacizumab (Avastin)
Inactivation
2. Receptor Binding/ EGFR Cetuximab (Erbitux)
Inactivation
3. Inhibition Of RTR EGFR Erlotinib (Tarceva)
Phosphorylation
4. Inhibition Of CTK bcr-abl Imatinib (Glevec)
Phsophorylation
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1. Alemtuzumab: (Campath)
A. Structure &Mechanism
1. Humanized IgG-1 Antibody
That Binds toCD-52 Antigen
On Malignant B & T Lymphocytes,
NK Cells, Monocytes, Macrophages
& Some Granulocytes
B. Uses:
1. B Cell Chronic Lymphocytic Leukemia
C. Side Effects:
1. Neutropenia
2. Anemia3. Thrombocytopenia
4. Opportunistic Infections Possible
2, Arcitumomab
A. Structure & Mechanism:
1. Murine Anti-Carinco-Embryonic Antigen Antibody
Labelled With 99m-Tecnetium.
B. Use:
1 Imaging Agent For: Metastatic Colorectal Cancer
C. Side Effects:
1. Due to Immunogeneicity Can Only
Be Given Once.
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3. Bevacizumab: ( Avastin)
A. Structure & Mechanism:
1. Humanized IgG-1 Antibody
2. Binds to Vascular Endothelial Growth
Factor and Inhibits VEGF From
Binding to Its Receptor Especially on
Endothelial Cells
3. Anti-Angiogenesis Effect
B. Uses:
1. Metastatic Colorectal Cancer
2. Lung Cancer
C. Precautions:1. Do Not Administer Until Patient
Recovers FromSurgery
2. Watch For Hemorrhage
3. Watch For GI Perforations
4. Watch For Wound Healing Problems
4. Capromab Pendetide
A. Structure & Mechanism:
1. Murine Monoclonal Antibody
Specific For Prostate Specific antigen
Coupled With 111-Indium.
B. Use:
1. Imunoscintigraphy:
A. Biopsy Confirmed Prostate Cancer &
B. Post Prostatectomy
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5. Cetuximab: (Erbitux): Metastatic Colorectal Cancer
A. Structure & Mechanism:
1. Human-Mouse Chimeric Antibody
That Targets the Epidermal Growth Factor Receptor
2. Thus Inhibits Tumor Cell Growth
Through a Variety of Mechanisms:
A. Decrease in Kinase Activity
B. Matrix Metalloproteinase Activity
C. Growth Factor Produciton
D. Increased Apoptosis
B. Metastatic Colorectal Cancers That
Overexpress EGFR.
6. Gemtuzumab: (Mylotarg) + Ozogamicin : CD33Acute Myelogenous
Leukemia
A. Structure & Mechanism:
1. Humanized Ig G-4 Antibody
Specific For CD33 , An SialoAdhesion
Protein Found on Leukemic Blast Cells
In 80-90% of Patients With :
Acute Myelogenous Leukemia
B. Uses:
1. CD 33: Acute Myelogenous Leukemia
(Patients >60 Years of Age) (First Relapses)
C. Side Effects:
1. Severe Myelosuppression
2. Significant Hepatotoxicity
3. Various Hypersensitivity Reactions
7. 90Y Ibritumomab: (Zevalin): Non Hodgkin Lymphoma
A. Structure & Mechanism:1. Murine Monoclonal Antibody Labeled With
Yttrium ( 90Y) or (111-In)
B. Uses:
1. Relapsed or Refractory Low Grade
Follicular or B Cell Non-Hodgkinss Lymphoma
2. Used in Conjunction with Rituximab (Rituxan)
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8. Rituximab: (Rituxan) Non-Hodgkin Lymphoma
A. Structure & Mechanism:
1. Chimeric Human-Mouse Monoclonal IgG-1 Antibody
That Binds to the CD20 Molecule on Normal
And Malignant B Lymphocytes
B. Mechanisms:
1. Complement Mediated Lysis
2. Antibody Dependent Cellular Cytotoxicity
3. Induction of Apoptosis of Malignant Lympoma Cells
C. Use:
1. Non-Hodgkins Lymphoma
D. Synergism:1. The Drug Appears to Be Synergistic
With Chemotherapy: (eg: Fludarabine,CHOP)
9. Iodine 131 Tositumomab: (Bexxar):
A. Structure & Mechanism
1. Anti-CD20 Monoclonal Antibody
Complexed with 131 Iodine
B. Use:
1. CD20- Positive Follicular Non-Hodgkins Lymphoma
C. Side Effects:
1. Cytopenias
A. Thrombocytopenia
B. Neutropenia
C. Etc.
10. Trastuzumab: (Herceptin): HER-2 Breast Cancer
A. Structure & Mechanism
1. Recombinant DNA Derived, Human
Monoclonal Antibody2. Binds to the HER-2 Domain of the
Epidermal Growth Factor Receptor
(EGFR) and Dowregulates the Receptor
B. Use:
1. Her-2/Neu Positive Metastatic Breast Cancer
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Monoclonal Antibodies:
As Immunosuppressants &
Anti-Inflammatory Agents:
1. Adalimumab: (Humira): Rheumatoid Arthirtis
A. Uses:
1. Rheumatoid Arthritis
2.Juvenile Rheumatoid Arthritis
B. Rare Side Effects: Reported:
1. Sudden Sepsis
2. Tuberculosis
3. Lymphoma
2. Etanercept (Enbrel):
A. Uses:
1. Rheumatoid Arthritis
2. Psoriatic Arthritis
3. Ankylosing Spondylitis
4. Chronic Plaque Psoriasis
B. Side Effects:
1. Monitor For:
A. Serious Infections
B. Malignancies: Eg: Lymphomas
3. Infliximab: Remicade
A. Uses
1. Rheumatoid Arthritis
2. Crohn Disease
3. Ulcerative Colitis
B. Major Side Effects
1. Rare Transfusion Reactions2. Delayed Serum Sickness
C. Rare Side Effects
1. Sudden Sepsis
2. Disseminated Mycobacterial Infections
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4. Abatacept: Orencia
A. Uses:
1. Rheumatoid Arthritis
Not Responsive to Other DMARDS
B. Serious Side Effects:
Monitor For:
1. Serious Infections:
A. Screen For Latent Tuberculosis
2. Use Caution in COPD
3. Possible Malignancies
5. Alafacept: Almevive
A. Mechanism1. Inhibits T Cell Activation
A. Binds to CD2: Cell Surface Antigen
B. Inhibits Normal CD2/LFA-3Interaction
B. Uses:
1. Chronic Plaque Psoriasis
C. Side Effects:
1. Malignancies
2. Infections
6. Efalizumab: (Rapitva)
A. Mechanism:
1. Binds to the CD11a Antigen
2. Inhibits Interaction of LFA-1
On All Lymphocytes With
Intercellular Adhesion Molecule-1
(ICAM-1)
3. Inhibits Adhesion, Activation, and
Migration of Lymphocytes into the Skin
B. Uses:1. Severe Psoriasis
C. Side Effects:
1. Increased Susceptibility to Infections
2. Thrombocytopenia (Rare)
3. Hemolytic Anemia: May Occur
After 4-6 Months of Treament
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7. Basilixiimab: (Simulect)
A. Mechanism:
1. IL-2 Antagonist
B. Uses:
1. Immunosuppressive:
A. Prophylaxis For Organ
Rejection in Renal Transplant Patients
C. Side Effects:
1. Incidence of Lymphoproliferative
Disorders Is Increased
2. Incidence of Opportunistic Infections
Increased
8. Daclizumab: ZenapaxA. Mechanism:
1. Binds to IL-2 Receptor
B. Uses:
1. Part of Immunosuppressive Regimen
Including Cyclosporine & Coriticosteroids
2. Prophylaxis For Organ Rejection
in Renal Transplant Patients
.
9. Omalizumab: (Xolair)
A. Mechanism:
1. Blocks Binding of IgE
to Fc (episilon) Receptor
on Mast Cells and Basophils
B. Uses:
1. Allergic Asthma.
C. Side Effects
1. Anaphylactic Reactions
Have Been Reported
2. Local Injection Site Reactions: 45%3. URI: 23%
4. Sinusitis: 16%
5. Pharyngitis: 11%
6. Viral Infections: 23%
D. Rare Side Effects:
1. Malignant Neoplasm: < 1%
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Other Monoclonal Antibodies:
1. Abciximab: (Reopro)
A. Mechanism:
1. Binds to the Intergrin GPIIB/IIIA
Receptor on Platelets &
Inhibits Fibrinogen
B. Uses:
1. An Adjunct to Heparin in Acute MI
2. Unstable Angina Not Responding to
Conventional Therapy When Percutaneous
Coronary Intervention is Scheduled Within24 Hours
C. Side Effects:
1. Increased Frequency of
Major Bleeding Complications:
Such As:
A. Pulmonary Bleeding
B. GI Bleeding
C. Retroperitoneal Bleeding
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Proteasome Inhibitors:
1. Bortezomib: (Velcade): Proteasome Inhibitor: Multiple Myeloma
A. Combination With Thalidomide + Dexamethasone: 92% Cure
Rate
B. Side Effects:
1. Peripheral Neuropathy
2. Orthostatic Postural Hypotension
3. Exacerbation of CHF
4. Use With Caution If:
A. Dehydration
B. History of Syncope
C. Medication Associated Hypotension
D. Hepatic or Renal Impairment5. Tumor Lysis Syndrome
6. Hematologic Toxicity Reported
A. Severe Thrrombocytopenia
7. CNS Disturbances:
A. Pyrexia: 25%
B. Psychiatric Disturbances: 35%
C. Headache: 25%
D. Etc.
2. Carfilzomib: Phase 1 Trials:
A. Uses
1. Prostate Cancer ( Partial Response)
2.Hematologic Cancers
3. Lactacystin Analog NPI-0052: Phase 1Trials:
A. Uses:
1. Hematologic Tumors
2. Solid Tumors
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Tyrosine Kinase Inhibitors:
1. Dasatinib: (Sprycel): Gleevec Resistant CML
Philadelphia Chromosome Positive ALL
2. Erlotinib: (Tarceva) Non Small Cell Lung Cancer
Pancreatic Cancer with Gemcitabine
A. Side Effects:
1. Edema (37% of Cases)
2. CNS Effects: : Fatigue, Dizziness, Headache,Insomnia
3. Pulmonary Toxicities: Rarely Reported:
A. Interstitial PneumoniaB. Interstitial Lung Disease
C. Pulmonary Fibrosis
D. Obliterative Bronchiolitis
4. Use With Caution in Liver Impairment
5. Uee With Caution in CVS Disease
6. Microangiopathic Hemmolytic Anemia With
Thrombocytopenai Reported With
Erlotinib + Gemcitabine Therapy
3. Gefitinib: (Iressa) (Epidermal Growth Factor):
: Non Small Cell Lung Cancer
A. Side Effects:
1. Rash: (43-54% of Cases)
2. Diarrhea: (48-76% of Cases)
3. Acne: (25-33% of Cases)
4. Pulmonary Toxicity: Rare
A. Interstitial Pneumonia
B. PneumonitisC. Alveolitis
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4. Imitinib: (Gleevec): Blast Phase of CML
A. Side Effects:
1. Nausea & Vomiting
2. Use With Caution in Fluid Retention Staates
A. Cardiovascular Disease
B. Pulmonary Disease
3. Diarrhea
4. Myalgias
5. Nilotinib: (AMN-107): Gleevec Resistant CML( Novartis Pharmaceuticals)
6. Sorafenib: (Nexavar): Advanced Renal Cancer
A. Mechanism:
1. Multikinase Inhibitor:
A. Intracellular raf Kinase Inhibitor
B. VEGF- R Inhibitor
C. c-KIT Receptor Inhibitor
D. FLT-3 Receptor Inhibitor
B Side Effects
1. Reversible Dose Limiting Toxicities Such As:
A. Diarrhea, Fatigue, Hand-Foot Syndrome
2. Hypertension
3. Cardiac Ischemia or MI
4. Serious Bleeding: Monitor PT/ INR
. in Patients on Warfarin (Coumadin)
5. Animal Studies: Teratogenicity & Fetal Loss
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7. Sunitinib: (Sutent) Advanced Renal Cancer and GIST
A. Mechanism:
1. Multi-Targeted RTK Inhibitor
A. VEGFR 1, 2, 3
B. c-KIT
C. PDGF Receptors
D. FMS Like Tyrosine Kinase -3 : (FLT-3)
E. CSF Receptor Type 1
F. Glial Cell Line Derived NeurotrophicFactor Receptor
(RET)
B. Side Effects:1. Monitor LVEF Function & Adjust
Dosage Accordingly or Interrupt Therapy
2. Hypertension: (15-28% of Cases)
3. Hemorrhagic Events Reported:
A. Upper GI Bleeding
B. Pulmonary Hemorrhage
C. Wound Bleeding
D. Rectal Bleeding
E. Epistaxis
F. Gingival Bleeding
4. Adrenal Function Abnormalities Reported:
A. Adrenal Insufficiency: With:
1. Trauma
2. Severe Infection
3. Undergoing Surgery
5. Skin or Hair Depigmentation or Discoloration Possible
6. Animal Studies: Teratogenicity and Fetal Loss
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Immunomodulatory Drugs:
1. Thalidomide + Dexamethasone
A. Use:
1. Multiple Myeloma
B. Toxicities:
1. Venous Thromboembolism
2. Neuropathy
3. Somnolence
4. Constipation
5. Rash
2. Lenalidomide+ Dexamethasone
A. Use:
1. Multiple Myeloma
2. MyelodysplaticSydromes
A. With Deletion Of 5q Cytogenetic Abnormalities
B. Under Investigation
1. RCC
2. Prostate Cancer
3. Hepatocellular Carcinoma
3. Phase II & III Trials:
A. Prostate Cancer
1. Docetaxel/Thalidomide
2. Docetaxel/ Bevacizumab
4. Phase II Trials:
A. Docetaxel/ Prednisone/ Thalidomide/ Bevacizumab
1. Androgen Independent Prostate Cancer
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Anti-Sense Agents
A. Oligonucleotides
1. Classification:
A. Peptide Nucleic Acids
B. Morpholino Oligonucleotides
C. Phosphorothioates
2. Phoshorothioates:
A. Binding Affinity To:
1. Heparin Binding Proteins
A. Basic & Acidic Fibroblast Growth Factor2. PDGF
3. VEGF
B. The Extracelular Matrix:
1. Laminin
2. Fibronectin
C. Mechanism Of Action:
1. Binds To First 6 Codons In Human bcl- mRNA
Eliciting Activity OF RNAase H
2. RNAase H : Cleaves The mRNA Strand Of
The mRNA-Oligonucleotide Complex.
3. Phosphodiesters & Phosphorothioates:
Are The Only Classes Of Oligonucleotides
Thar Elicit RNAase Activity.
3. Clinical Trials With Oblimersen: G3139
1. Chronic Lymphocytic Leukemias
A. In Combination Chemotherapy :
1. Fludarabine + Cyclophosphamide
2. Complications:A. Catheter Related Complications
B. Hematologic:
1. Thrombocytopenia
2. Febrile Neutropenia
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4. Clinical Trials With Oblimersen: G3139:
1. Advanced Melanoma
A. In Combination Chemotherapy:
1. Dacarbazine + Oblimersen
B. Toxicities:
1. Bleeding Problems
2. Catheter Related Events
A. Venous Thrombosis
B. Occlusion
C. Infections
5. Oblimersen :A. Is The First Oligonucleotide To Demonstrate
Proof Of The Principle OF An Anti Sense
Effect in Human Tumors By Down Regulation
Of Target Bcl-2 Protein.
B. The Bcl-2 Protein Is Overexpressed In Several Cancers
& Is Implicated IN Anti-Apototic Pathways.
6. Oblimersen (Genasense)
A. Is Being Studied For Treatment Of Several Cancers
Including Hematologic Cancers & Solid Tumors
With Combination Chemotherapy.
7. Fomivirsen:
A. FDA Approved Drug For:
1. CMV Retinitis In AIDs Patients
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Investigational Anti-Angiogenesis Agents:
Drug Cellular Targets
1. Anti-VEGF Agents
A. VEGF-AS (Anti-Sense Oligonucleotides) VEGF, VEGF-C
VEGF-D
B. VEGF Trap VEGF, PLGF
2. Multi-Targeted Agents That Interfere
With Growth Factor Receptor
Signalling Pathways
A. Axitinib VEGFR-1.
VEFGR-2, PDGFR
B. AZD-2171 VEGFR-1, 2, &3
PDGFR, c-KIT
C. BMS-582664 VEGFR-2, FGFR
D. Motesanib VEGFR-1, 2 , 3
PDGFR, c-KIT
E. OSI-930 VEGFR-2, c-KIT
F. Pazopanib VEFGR-2
G. RPI-4610 (Angiozyme) mRNA For VEGFR-1
H. Tandutinib FLT-3, PDGFR,C-KIT
I. Vatalanib VEGFR-1, 2, 3 , PDGFR
c-KIT
J. Vandetanib VEGFR -1,2, 3
K. XL- 184 VEGFR-2, MET, c-KIT,
FLT- 3, TIE-2
L. XL- 999 VEGFRs, FGFRs,
PDGFR, FLT-3
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3. Agents Target Other Proteins
Or Pathways:
A. AMG-386 Angiopoietins
B. AMG- 479 Insulin Like Growth
Factor -1 Receptor
C. ATN- 161 Alpha-5 Beta- 1
Integrin Receptor
D. CP- 751871 Insulin Growth Factor-1 Receptor
E. Volociximab Alpha-5-Beta-1
Integrin Receptor
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Examples Of Drugs That Posses Anti-Angiogenic Activity
Or Inhibit Angiogenesis As A Secondary Function:
Drug Class
1. Cetuximab EGFR/HER Monoclonal
Panitumumab Antibodies
Trastuzumab
2. Gefitinib EGFR Small MoleculeErlotinib Receptor Tyrosine Kinase
Inhibitors
3. Everolimus mTOR Inhibitors
Temsirolimus
4. Belinostat HDAC Inhibitors
LBH-589
Vorinostat
5. Celocoxib COX-2 Inhibitor
6. Bortezomib Proteasome Inhibitor
7. Zolendronic Acid Bisphosphonates
8. Rosiglitazone PPAR-Gamma Agonists
9. Doxycyline Antibiotics
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Examples Of Endogenous Angiogenesis Inhibitors:
1. Alphastatin
2. Angiostatin
3. Antithrombin III
4. Arrestin
5. Candstatin
6. Endostatin
7. Interfron Alpha Or Beta
8. 2-Methoxy-Estradiol
9. Pigment Epithelial Derived Factor
10. Tetrahydrocortisol
11. Thrombospondin
12. TIMP-2
13.Tumstatin
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Preventive Cancer Vaccines:
1. Hepatitis B Vaccine
2. HPV Vaccine
3. Vaccine In Preparation For H. Pylori
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Histidine Deacetylase Inhibitors
(HDAC Inhibitors)
1. Mechanism:
A. Effects On Non-Histone Proteins
Related To Acetylation
B. Alter The Degree Of Acetylation
On Non-Histone Proteins
& Thereby Repress Or Increase Their Activity
2. First Generation Inhibitors:
A. Small Chain Fatty Acids
1. Sodium Butyrate
A. Phase 1 Studies: Refractory AML2. Arginine Butyrate
3. Sodium Phenylbutyrate
A. Phase 1 Studies: AML
Myelodyspalstic Syndromes
B. Phase 1 Studies: Papillary Thyroid Cancer (Partial Response)
Mesothelioma (Partial Response)
Laryngeal Cancer (Partial Response)
4. Valproic Acid With All-Trans Retinoic Acid
A. AML
B. Myelodysplastic Syndromes
3. Second Generation Inhibitors:
A. Hydroxamic Acids: (Class 1 &2)
1. Vorinostat: (Class 1&2)
1. FDA Approved For:
A. Cutaneous T-Cell Lymphoma
2. Toxicities:
A. Fatigue
B. Nausea/Vomiting/C. Thrombocytopenia
3. Phase 1 Trials:
1. Hodgkins Lymphoma
2. Non-Hodgkins Lymphoma
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B. Cyclic Tetrapeptides:
1. Romidepsin: (Class 1&2)
A. Phase 1 Trials: Renal Carcinoma
B. Phase 2 Trials: Cutaneous T Cell Lymphoma
C. Side Effects:
1. EKG Changes:
A. T Wave Flattening
B. ST-T Wave Depressions
C. No Changes In LV Ejection Fractions
D. No Changes In Serum Cardiac Troponin Levels
C. Benzamides:1. SNDX275 (Class 1)
A. Phase 1 Trials: Relapse & Refractory AML
B Side Effects:
1. Infection
2. Unsteady Gait
3. Somnolence
D. Pharmocodynamic Changes Associated With HDAC Inhibitors:
1. Vorinostat (Class 1 &2)
A. Transient Increase In Acetylation Of Histone 3
In Peripheral Lympocytes
B. Translocation Of Phosphorylation STAT-3 From Nucleus
To Cytoplasm
2. Romidepsin:
A. Induced Histone Acetylation Of H3 &H4 In Peripheral
Blood Tumor Cells
B. p21 Protein Levels Increased Associated With Increased
Histone 4 Levels At The p21 Promoter Region
3. SNDX275:A. Increased Histone H3 & H4 Acetylation
B. Increased p21 & Activation Of Caspase 3
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DNMT Inhibitors + HDAC Inhibitors:
1. First Studies:
A. 5AC + Sodium Phenylbutyrate:
1. Uses: AML
Myelodysplastic Syndrome
2. Similar Study:
A. Decitabine + Valproic Acid +All Trans Retinoic Acid:
1. Uses: AML
Myelodsyplastic Syndrome
3. Ongoing Studies:
A. Combination Of DNMT Inhibitors +Second Generation HDAC Inhibitors:
Including:
1. SNDX-275 (Class 1)
2. Vorinostat (Class 1&2)
3. Belinostat (Class 1&2)
4. MGCD-0103 (Class 1)
DNA Methyltransferase Inihibtors:
1. 5-Azacitidine
A. Uses:
1. Myelodysplastic Syndrome
2. Investigational Uses:
A. Refractory ALL &AML
2. 2-Deoxy 5-Azactyidine
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Aurora Kinase Inhibitors:
1. The Auroras Are Involved In Regulation
Of Multiple Steps In Mitosis Including:
A. Centrosome Duplication
B. Formation Of The Bipolar Mitotic Spindle
C. Chromosomal Alignment on The Mitotic Spindle
D. Fidelity Of Spindle Checkpoint.
2. Aurora Proteins :
A. Belong To A Family Of Serine/Threonine Kinases
That Are Regulators Of Different Steps In Mitosis
3. Mechanism Of The Inhibitors
A. Targets Enzymes Central To Cellular Mitosis.
4. Inhibitors:
A. ZM447439
B. Hesperadin
C. VX- 680
Serine/Threonine Kinase Inhibitors;
1. Enzastaurin:
A. Oral Agent
B. Mechanism:
1. Induces Tumor Cell Apoptosis
2. Inhibitis Proliferation And Angiogenesis
C. Uses:
1. Second Or Third Line TherapyOf Non-Small Lung Cancer
2. Phase 1/2 Clinical Trials With
Temolozomide & RadiationTherapy
For Glioblastoma Multiforme
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Protein Tyrosine Phosphatase Inhibitors:
1. Sodium Stibogluconate:
A. SSG + Interferon Alpha 2b: Clinical Trials:
1. Inhibits The Following Cancers;
A. Melanoma
B. Colorectal Cancer
C. Squamous Cell Carcinoma Of The Head & Neck
D. Peritoneal Mesothelioma
E. Ovarian Cancer
Hedgehog Antagonists
1. Clinical Trials: Phase 2 Trials
A. With Avastin (Bevacizumab)For First Line Therapy For
Metastatic Colorectal Cancer
Gene Therapy:
1. Gene Augmentation Therapy
A. Is Appropriate For Treatment Of Inherited
Disorders Caused By A Loss Of A Functional
Gene Product.
2. Gene Inhibition Therapy:
A. Is Suitable For Treatment Of Infectious Diseases.
Cancer, & Inherited Diseases.
3. It Is Very Important To Ensure That Suicide Genes
Are Very Appropriately Targeted.
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Immunotherapy:
1. Non Antigen Specific Therapies:
A. Interleukin 2 Therapy:
1. 10-20% Tumor Regression:
A. Melanoma
B. Renal Cancer
B. Anti CTLA-4 Blocking Antibodies
In Combination With Anti CD-25
Antibody & Tumor Vaccines:
1. Show Regression In Murine Tumor Systems
C. Peptide Vaccines
D. Whole Cell Vaccines:1. Canvaxin Trials:
A. 3 Inactivated Allogenic Melanoma Cells
With BCG : Overall Survival: 49%
E. Dendrite Vaccines
F. Recombinant Vaccines:
1. Consist Of :
A. Recombinant Viral Constituents Or
Naked DNA.
B. Contained
1. Full Length Gene Products
G. Heat Shock Protein Vaccines (Oncophage)
1. Numerous Trials Have Failed To
Demonstrate Effectiveness
H. Lymphoma Vaccine: Clinical Trials
1. Shows Promise In Lymphoma
I. Her+2 GM-CSF Secreting Breast Tumor Vaccine:
1. Clinical Trials: With Cyclophosphamide
J. CD4+ T Helper Peptides : Clinical Trials:
1. Evaluation For Her2-Neu Breast CancerK. IGN 101 Cancer Vaccine:
1. Clinical Trials: For
A. Epithelial Cancers
1. Acting On Epithelial Cell Adhesion Molecules
.
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L. Passive Immunological Rx:
1. Lymphokine Activated Killer Cells To Syngenic
Mice + Interleukin 2
A. Regression Of Pulmonary Metastases
2. Allogeneic Hematopoietic Stem Cell Transplants:
A. For Leukemias
M. Antibody Based Therapies:
1. Herceptin: Trastuzumab: Her-Neu-2 Breast Cancer
2. Rituxan: Rituximab: B Cell Leukemia
K. Loss Or Down Regulation Of Class 1 HistocompatibilityLeukocyte Antigens
1. Recent Studies :
NK Cells Express Receptors
(NKG2D) Which Bind To Stress Induced Ligands
That Can Be Upgraded In A Variety Of Tumors.
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Oncogenic Infectious Agents
Agent Tumor Type
1. Bacteria
A. H. Pylori Stomach Cancer,
Gastric Lymphoma
2. Viruses:
A. Human Papilloma Cervical Cancer,
Virus Vaginal Cancer,
Anal Cancer
B. Hepatitis B Virus Liver Cancer
C. Hepatitis C Virus Liver Cancer
D. HIV Kaposi Sarcoma,
NHL
E. Human Herpes Type 8 Kaposi Sarcoma
F. Epstein Barr Virus Nasopharyngeal Carcinoma
Lymphomas: Hodgkins and
Non-Hodkgins Lymphomas
G. Human T Cell
Lymphotrophic Virus-1 Adult T Cell Leukemia
3. Parasites:
A. Schistosomiasis Bladder Cancer
B. Liver Flukes Cholangiocarcinoma
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Major References:
1. Lacy et al: Drug Information Handbook 14th Edition: 2006
2. De Vita, Lawrence & Rosenberg; Cancer: Principles Of Oncology: 2008
3. www.asco.org
4. http://en.Wikipedia.org/wiki/AntiSense_Therapy
5. Clinical Cancer Research Vol 10,4245S-4248S, June 15,2004
Herbst & Frankel et al: Proceedings of the First International Conference
Oblimersen Sodium:Genasense bcl-2 Anti Sense Oligonucleotides
6. Monday Dec 10, 2007 News-Medical.Net
Complete Response With Oblimersen Combination Improves Survival
In CLL Patients7. Maxon & Weaver MD: CancerConsultants.com
Anti -Sense Therapy:Overview
8. http://www.medscape.com/viewsarticle/495344
Keen & Taylor:Aurora Kinase Inhibitors As Anti-Cancer Agents
9. http:// en.wikipedia.org/wiki/Aurora_inhibitors
10. http://ghr.nlm.nih.gov/handobook/therapy? Show =all
Genetics: Home Reference: US National Library Of Medicine
GeneTherapy
11. http://www.biooncology.com/bioonc/research/hedgehog/index.m?s_cid=
0001&s_src=go
Genetech BioOncology:
Cell Differentiation , Growth & Proliferaiton:
Hedgehog Antagonists
12.http://wwwabcam.com/index.html?pageconfig=resource&rid=10858&pid
=10039
Abcam: Hedgehog Signalling Cascade
13. http//clinicaltrials.gov/ct2/show/NCT00636610?term=hedgehog&rank=1
Clinical Trials.gov
A Study of Systemic Hedgehog Anataonists With ConcurrentChemotherapy & Bevacizumab As First Line Therapy For Metastatic
Colorectal Cancer
14. http://en.wikipedia.org/wiki/Hedgehog_signalling_pathways
15. http://theoncologist.alphamedpress.org/cgi/contnet/full/8/4/389
The Oncologist, Vol 8, No 4,389-391August ,2003
D. Goodsell: The Molecular Perspective: Histone Deacetylase
http://www.asco.org/http://en.wikipedia.org/wiki/AntiSense_Therapyhttp://www.medscape.com/viewsarticle/495344http://wwwabcam.com/index.html?pageconfig=resource&rid=10858&pidhttp://theoncologist.alphamedpress.org/cgi/contnet/full/8/4/389http://www.asco.org/http://en.wikipedia.org/wiki/AntiSense_Therapyhttp://www.medscape.com/viewsarticle/495344http://wwwabcam.com/index.html?pageconfig=resource&rid=10858&pidhttp://theoncologist.alphamedpress.org/cgi/contnet/full/8/4/389 -
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16. hhtp://en.wikipedia.org/wiki/Histone_deacetlyase
17. http://jco.ascopubs.org/cgi/content/abstract/26/7/1135
Y.Oh, R. Herbst et .al : Enzastaurin, An Oral Serine/Threonine
Kinase Inhibitor As Second Or Third Line Therapy Of
Non-Small Cell Lung Cancer
http://jco.ascopubs.org/cgi/content/abstract/26/7/1135http://jco.ascopubs.org/cgi/content/abstract/26/7/1135