Oncology Exam 1

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Oncology Exam 1
2012-01-28 18:59:37

Dr. Schiff Notes; Introduction to Oncology; Monoclonal Antibodies
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  1. Source: Plant-derived alkaloid – Catharanthus roseus

    (L.) G. Don (Fam.Apocynaceae)
    Vinblastine & Vincristine
  2. Chemistry– Bisindole alkaloid (minor)• Indole-dihydroindole (indole-indoline)• Yield = 0.001-0.002 % - VERY EXPENSIVE

    – Commercial production• Isolate monomeric alkaloids that occur in fargreater amounts from the same plant• Combine the monomers via semi-synthesis• Top portion of VLB = Catharanthine monomer• Bottom portion of VLB = Vindoline monomer
    Vinblastine & Vincristine
  3. Chemistry– Indole nitrogen does not form salts withacids• Unshared nitrogen electron pair is delocalized– Dihydroindole (indoline) nitrogen atom issufficiently basic to form salts with acids– Close structural relative of vincristine• Differs only in the degree of oxygenation of theN-1 carbon– Colorless• No colored metabolites in body excretions– Marketed as its water soluble sulfate salt
    Vinblastine & Vincristine
  4. MOA: Inhibit microtubule function; bind to tubulin at interface of heterodimers to promote microtubule dissolution - antimitotics
    Vinblastine & Vincristine & Vinorelbine & Vinflunine & Vindesine
  5. Common Applications:
    -Lymphomas (hodgkin's, non-Hodgkin's)
    -breast carcinoma
    -testicular carcinoma
  6. Special Adverse Effects:
    -Hypotension (most common cardiovascular adverse effect - due to autonomic dysfunction)
    -Constipation -- start of therapy includes a bowel regimen of high-fiber diet/med +stool softeners
    -Vesicant -- extravasation (skin damage, inflammation, necrosis) [extravasation is treated with heat + local hyaluronidase inj.]
  7. Chemical difference between Vinblastine and Vincristine
    Vincristine has the presence of a N-1 CHO and Vinblastine has a N-1 CH3
  8. Common Applications:
    -Lymphomas (Hodgkin's & non-Hodgkin's)
    -Acute leukemia
    -Many others
    - "MOPP" combination
  9. Special Adverse Effects:
    -Peripheral/central neuropathies (tingling in the extremities; sever jaw pain; constipation may be severe)
    -Vesicant (like VLB)
    -Minimal myelosuppression (unlike VLB)
  10. Source: Semi-synthetic from vinblastine
  11. Chemistry:
    – Same as vinblastine, except
    • “Nor” – without CH2 group at C-8’
    – Nor = N ohne radikale
    • Notice dehydration across the C-3’/C-4’ bond
    – Marketed as its water soluble tartrate salt
  12. Common Applications:
    -Non-small cell lung cancer (NSCLC)
    -Metastatic breast cancer
    -Ovarian/uterine cancer
    -Used in relapsed/advanced cases
  13. Special Adverse Effects:
    - Shares same as both vinblastine and vincristine (peripheral neuropathies + vesicant)
  14. Source:
    – Semi-synthetic
    – Fluorinated analog of the semi-syntheticalkaloid vinorelbine
  15. Chemisty:
    – Difluoro-substitution on CH2 group of C-4’ethyl chain
    – Marketed as water soluble ditartrate salt
  16. Common Applications:
    -Phase 2 - Metastatic breast carcinoma in patients whose cancer has recurred or progressed following prior therapy with anthracyclines and taxanes
    -Phase 2 - Primary therapy of mesothelioma
  17. Special Adverse Effects:
    - Same as other Vinca alkaloids
  18. Source:
    -semi-synthetic from vinblastine
  19. Chemistry:
    – Deacetylvinblastine carboxamide
    • Deacetyl- at C-4
    • Carboxamide at C-3
    – Marketed as its water soluble sulfate salt
  20. Common Applications:
    -Metastatic breast cancer
    -Lung cancer
  21. Special Adverse Effects: Shares same as both vinblastine and vincristine (peripheral neuropathies)
  22. –any abnormal swelling in or on a part of the body

    –cells multiplying abnormally
  23. non-cancerous, encapsulated and localized tumors
    Benign tumors
  24. describes a tumor that invades and destroys the tissue in which it originates and can spread to other sites in the body via the bloodstream and lymphatic system
    malignant tumor
  25. the study and practice of treating malignant tumors
  26. the distant spread of malignant tumor from its site of origin
  27. any cancer that arises in epithelium, the tissue that lines the external and internal organs of the body
  28. cancer that arises in the blood and is immune-system related
  29. a single cell exposed to a carcinogen resulting in genetic changes
  30. certain carcinogens or other factors that a person has been exposed to --- leads to further progression of the growth of the carcinogens
  31. the cell leading to further proliferation and active progression into a tumor, etc.
  32. The immune response to cancer is largely ______ mediated

    These types of cells take over:
    1) T-cell mediated

    2) tumor associated antigens
  33. Exposure to cancer can be influenced by all these different factors:
    • •Diet
    • •Genetic factors
    • •Mutagens
    • •Drugs – alkylating agents and anthracyclines
    • •Carcinogens–Chemicals - Benzene–Radiation–Ultraviolet light
    • •Oncogenic viruses–chronic infections in a cell–produce virally encoded proteins that override or interfere with the cell’s normal mechanisms for regulating cell division
  34. •Develop from normal genes that regulate normal cellular function called protooncogenes
    •Code for proteins such as: growth factors, growth factor receptors, nuclear regulatory proteins, cell-cycle regulators, and signal transducing proteins
  35. Encode proteins that prevent unwanted cellular growth and proliferation of mutant cells

    Ex. Growth-inhibitory factors, proteins involved in cell cycle regulation, proteins involved in apoptosis
    Tumor Suppressor Genes
  36. Gompertz and Cell Population Growth
    • Cancer cells do not stop multiplying when they reach a "critical mass"
    • -- early stage is exponential growth
    • -- at later stages the doubling time increases (tumor cell never stops growing)

    Apoptosis is lossed
  37. The process by which as a tumor grows, blood vessels begin to grow and develop on the tumor, which can lead to metastasis
  38. Pha, ses of the Cell Cycle
    Mitosis (M), Resting phase (G0), Growth phase (G1), Synthesis phase (S), Second growth phase (G2)
  39. The part of the cell cycle when cell division occurs
    Mitosis (M)
  40. The part of the cell cycle that is known as the dormant phase
    Resting phase (G0)
  41. The part of the cell cycle where the cell is preparing for DNA synthesis
    Growth phase (G1)
  42. The part of the cell cycle when DNA synthesis occurs
    Synthesis phase (S)
  43. The part of the cell cycle when the cell is preparing for mitosis and is producing RNA
    Second growth phase (G2)
  44. Transitions through the phases of the cell cycle are controlled by these two things:
    • 1) cyclin-dependent kinases (CDKs)
    • 2) cyclin-dependent kinase inhibitors
  45. 5 Different approaches to Cancer Treatment
    • 1. Pharmacotherapy
    • 2. Radiation
    • 3. Surgery
    • 4. Combination therapy
    • 5. No treatment
  46. Intent of Therapy is to eliminate all cancer
    Curative intent
  47. Initial treatment to reduce a cancer, which is followed by other treatments
    induction therapy
  48. a type of chemotherapy used after curative methods such as surgery
    adjuvant therapy
  49. a type of cancer therapy to be used before curative methods such as surgery
    neo-adjuvant therapy
  50. Therapy intended to maintain a disease free state
    maintenance therapy
  51. Treatment that is given after cancer has disappeared following the initial therapy
  52. Intent of therapy to minimize growth and/or effets of cancer (control, symptom management, and clinical benefit)
    Palliative therapy
  53. Rituximab MOA
    • – Directed against the CD20 antigen on Blymphocytes
    • – Binds to the antigen on the cell surface,activating complement-dependentcytotoxicity
    • – Human Fc receptors – mediates cell killingthrough an antibody-dependent cellulartoxicity
  54. Rituximab Indications:
    • – Non-hodgkin’s lymphoma (NHL)
    • • Follicular lymphoma
    • • Low-grade lymphoma (other than follicular)
    • • High-grade lymphoma

    • – Multiple myeloma (MM)
    • – Chronic lymphocytic leukemia (CLL)
    • – Post-transplant lymphoproliferative disorder (PTLD)
    • – Idiopathic thrombocytopenic purpura (ITP)
    • – Thrombotic thrombocytopenic purpura (TTP)
    • – Glioblastoma
    • – Metastatic renal cell carcinoma
    • – Hemophilia
  55. Rituximab Adverse Effects
    • – Infusion related reactions
    • • chills, fever, rigors, dizziness, hypotension, bronchospasm, nausea/vomiting, pruritis
    • – Fever
    • – Mucocutaneous reactions
    • • Rash, pruritis• Severe- stevens-johnson syndrome
    • – Infection
    • – Hematologic toxicity
    • – Tumor lysis syndrome
    • – Acute renal failure
    • – Hepatits B reactivation
    • – Progressive multifocal leukoencephalopathy(PML)
    • – Bowel obstruction and perforation
  56. Premedications required with Rituximab
    Acetaminophen and Diphenhydramine
  57. Should meds be held prior to treatment with Ritxuimab?
    Yes --- consider withholding antihypertensives 12 hours prior to treatment
  58. 131 I-tositumomab (Bexxar®) MOA:
    • –induction of apoptosis
    • –complement-dependent cytotoxicity
    • –ADCC
  59. 131 I-tositumomab (Bexxar®) Indications
    –CD20 antigen-expressing relapsed or refractory, low grade follicular, or transformed non-Hodgkins’s lymphoma (NHL)

    –Rituximab-refractory NHL
  60. Premedications used with 131 I-tositumomab (Bexxar®)
    Acetaminophen 650 mg PO x 1

    Diphenhydramine 50 mg PO x 1
  61. 131 I-tositumomab (Bexxar®) Drug Interactions:
    use caution with other medications that interfere with platelet fxn and/or anticoagulation because Bexxar causes hematologic toxicities
  62. 131 I-tositumomab (Bexxar®) Side Effects:
    • –hypersensitivity reactions
    • –decreased white blood cells (WBC)
    • –decreased red blood cells (Hgb)
    • –decreased platelets
    • –secondary malignancies
    • –hypothyroidism
    • –Gastrointestinal toxicity
    • –Infusion related toxicity
  63. Ibritumomab Tiuxetan (Zevalin®) MOA:
    –complementary-determining regions of Ibritumomab bind to the CD20 antigen on B lymphocytes

    –induces apoptosis in CD20+ B-cell lines

    –beat emission from Y-90 induces cellular damage by the formation of free radicals in the target and neighboring cells
  64. Ibritumomab Tiuxetan (Zevalin®) Drug Interactions:
    watch when administering with other medications that interfere with platelet function and/or anticoagulation
  65. Ibritumomab Tiuxetan (Zevalin®) Indications:
    –relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma

    –rituximab refractory follicular non-Hodgkin’s lymphoma
  66. Ibritumomab Tiuxetan (Zevalin®) Side Effects:
    • –infusion reactions
    • –decreased platelets
    • –decreased white blood cells
    • –decreased red blood cells
    • –erythema, Stevens Johnson syndrome, dermatitis
    • –secondary malignancies
    • –gastrointestinal symptoms
  67. Alemtuzumab (Campath®) MOA:
    • –Binds to CD52
    • •CD52 is a nonmodulating antigen present on the surface of essentially all B and T lymphocytes, a majority of monocytes, macrophages, NK cells, and a subpopulation of granulocytes

    –Results in an antibody-dependent lysis
  68. Alemtuzumab (Campath®) Indications:

    ***do not administer as IVP or IV bolus***
    B-cell chronic lymphocytic leukemia (CLL)
  69. Alemtuzumab (Campath®) Toxicities
    Infusion related reactions

    Bone marrow suppression

    Immunosuppression -- must prophylax patietns with Bactrim due to this side effect
  70. Alemtuzumab (Campath) Premedications:
    Acetaminophen and Diphenhydramine
  71. Ofatumumab (Arzerra®) MOA:
    Ofatumumab binds specifically to both the small and large extracellular loops of the CD20 molecule
  72. Ofatumumab (arzerra) indication:
    CD20-directed cytolytic monoclonal antibody indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab.
  73. Ofatumumab (Arzerra) Premedications:
    • Oral Acetaminophen
    • Oral or IV antihistamine
    • IV corticosteroid
  74. Ofatumumab (Arzerra) Side Effects:
    • Infusion Reactions
    • Neutropenia
    • Thrombocytopenia

    Many others
  75. Trastuzumab (Herceptin®) MOA:
    –Binds to the extracellular domain of the human epidermal growth factor receptor 2 (HER-2)

    –Mediates antibody-cellular cytotoxicity against cells which overproduce HER-2
  76. Trastuzumab (Herceptin®) Indication:
    –adjuvant treatment of HER2-overexpressing breast cancer

    –HER2-overexpressing metastatic breast cancer

    –the treatment of HER2-overexpressing metastatic gastric cancers
  77. Trastuzumab (Herceptin®) Adverse Effects:
    Hypersensitivity Reactions

    Cardiac toxicity

    Exacerbation of chemo-induced neutropenia
  78. Bevacizumab (Avastin®) Indication:
    • •Colorectal cancer
    • •Renal cell cancer
    • •Lung Cancer
    • •Ovarian Cancer
    • •Acute leukemia
    • •Caution: Breast cancer
  79. Bevacizumab (Avastin) Toxicities:
    • –hypertension
    • –proteinuria
    • –thromboembolic event (DVT or PE)
    • wound healing complications (do not administer until 4 weeks after a surgery)
    • –gastrointestinal perforations
    • –hemorrhage
  80. Cetuximab (Erbitux®) Indication:
    Colorectal cancer

    Head and neck cancer
  81. Cetuximab (Erbitux®) Toxicities:
    • - Dermatologic
    • - Infusion reactions
    • – electrolyte abnormalities
    • – pulmonary toxicity
  82. Panitumumab (Vectibix™) MOA:
    – binds specifically to the human EGFR

    – signal transduction through the EGFR results inactivation of wild-type KRAS protein
  83. Panitumumab (Vectibix™) Indications:
    – + EGFR expression – patients must be tested for EGFR expression

    – metastatic colorectal cancer with diseaseprogression on standard therapies
  84. Panitumumab (Vectibix™) Toxicities:
    • – Infusion reactions
    • – Dermatologic >90%
    • • acneiform, pruritis, erythema, rash, dry skin
    • – Ocular
    • • conjunctivitis, ↑ lacrimation
    • – Abdominal pain
    • – Diarrhea
    • – Hypomagnesemia
    • – Pulmonary fibrosis <1%
    • – Photosensitivity
    • – Impairment of fertility
  85. Denosumab (Xgeva™) MOA:
    Binds to human RANKL, a transmembrane (soluble protein) essential for the formation, function, and survival of osteoclasts

    Prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors
  86. Denosumab (Xgeva™) Indication:
    Prevention of skeletal-related events in patients with bone metastases from solid tumors

    NOT indicated for the prevention of skeletal-related events in patients with multiple myeloma
  87. Denosumab (Xgeva™) Adverse Effects:
    • –fatigue/asthenia
    • –nausea
    • –hypophosphatemia
    • –hypocalcemia
    • osteonecrosis of the jaw (ONJ) – good oral hygeine, no invasive dental procedures
  88. Ipilimumab (Yervoy™) MOA:
    Binds to the cytotoxic T-lymphocyte associated angiten 4 (CTLA-4).

    CTLA-4 is a negative regulator of T-cell activation.

    Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands (CD80/CD86).
  89. Ipilimumab (Yervoy™) Indication:
    Treatment of unresectable or metastatic melanoma
  90. Ipilimumab (Yervoy™) Adverse Effects:
    • –Immune- Mediated
    • –Enterocolitis: Diarrhea, abdominal pain
    • –Hepatotoxicity: Hepatitis
    • –Dermatitis
    • –Neuropathy
    • –Endocrinopathy: Hypopituitarism & Adrenal Insufficiency
  91. Brentuximab (Adcetris™) MOA:
    Directed against CD30

    Small molecule MMAE is a microtubule disrupting agent

    Brentuximab binding of the ADC to CD30, followed by internalization of the ADC-CD30 complex, and the release of MMAE via proteolytic cleavage
  92. Brentuximab (Adcetris™) Adverse Reactions:
    • –Neutropenia
    • –Thrombocytopenia
    • –Anemia
    • –Peripheral sensory neuropathy
    • –Nausea/vomiting
    • –Fatigue
    • –Diarrhea
    • –Upper respiratory infection
    • –Rash
    • –Fever
    • –Infusion reactions
  93. Vinca Alkaloid Resistance occurs by:
    • Increased expression of the multidrug-resistant gene with elevated P170 glycoprotein levels, leading to
    • –Enhanced efflux of drug
    • –Decreased intracellular drug accumulation
  94. Source:
    –Plant-derived alkaloid
    –Camptotheca acuminata Decne (Fam Nyssaceae)
    –Chinese ornamental, introduced into the USA in 1911
  95. Chemistry:
    – Pyrrolo[3,4-b]quinoline alkaloid
    – Very low water solubility
    – The naturally occurring (S)-isomer issignificantly more bioactive than the (R)-isomer
    – Intact lactone mandatory for bioactivity butis a liability in aqueous solution becauseof hydrolysis and ring opening
    – Physiologic pH favors the ring-openedlactone (carboxylate) which is 1000x lesspotent
  96. MOA: These agents stabilize the cleavablecomplex in which topoisomerase I iscovalently bound to DNA at a singlestrandedbreak site
    – The flat camptothecin ring systemintercalates DNA at the site of cleavage,mimicking a DNA base pair
    – Lethal DNA damage follows
    Camptothecin, Topotecan, Irinotecan
  97. Source: Semi-synthetic analog of camptothecin(1989)
  98. Chemistry: (S)-9-Dimethylaminomethyl-10-hydroxycamptothecin
    – Low water solubility
    – Forms nicely water soluble HCl salt at C-9dimethylamino- group
  99. Common applications:
    – Ovarian cancer
    – Small-cell lung cancer
    – Acute myelogenous leukemia (AML)
    – Glioma: Via convection-enhanced delivery (slowinfusion of drug directly into tumor andsurrounding brain through implantation of catheter into the interstitial space)
  100. Special Adverse Effects:
    – Anemia (40-95%)
    – About 50% of patients require erythrocyte(RBC) transfusions
  101. Source:
    – Semi-synthetic analog of camptothecin(1985)
    – First camptothecin with increased watersolubility
    – Japan – 1987
    – Therapeutic use: Japan in 1994; USA in Mid- 1990’s
  102. Chemistry:
    – Pale yellow
    – Low water solubility
    – (S)-7-Ethyl-10-hydroxycamptothecin-10-[1,4’]-bipiperidine-1’-carboxylate
    • Water soluble HCl salt at the basic piperidine N
    – Pro drug of a previously prepared analog
    • 7-Ethyl-10-hydroxycamptothecin (1,000x moreactive than irinotecan)
  103. Common Applications
    Colorectal cancer
    – Small cell and non-small cell lung cancer
    – Glioblastoma: With bevacizumab to extend survival
  104. Special Adverse Effects:
    – Like topotecan
    – Diarrhea (15-25%) Dose-limiting; can be severe; potentially fatal; Attributed to acetylcholinesterase inhibition: Use loperamide (Imodium® )
    – Interstitial pulmonary disease (2010)
  105. Source: A semi-synthetic camptothecin (9-nitrocamptothecin) for oral admin.

    Orphan Drug
    – Therapy of pancreatic cancer patients whohave failed at least one priorchemotherapy
    – HIV- and AIDS-infected pediatric patients
  106. Resistance to this drug is caused by: Decreased expression of topoisomerase I

    Mutations in topoisomerase I with decreased binding affinity of drug
  107. Resistance to this drug is the same as Topotecan -- Increased expression of the multidrugresistantgene with elevated P170 glycoprotein levels, leading to
    – Enhanced efflux of drug
    – Decreased intracellular drug accumulation

    Decreased activity or expression ofcarboxylesterase enzyme – decreasedSN-38
  108. Source:
    –Plant-derived alkaloid
    –Taxus brevifolia Nutt. (Fam. Taxaceae)
    –Pacific Yew: A slow-growing evergreen
    –May be isolated from other Taxus spp: Taxus baccata – European Yew
  109. Source:
    –A new source is the Red Yew that is being grown at Lam Dong Research Center in North Vietnam
    –Taxus wallichiana Zucc. (Fam. Taxaceae)
    –Growth via “layering technique” : pull leaves down to touch the ground and take root
    –Taxol content – 2-4x higher than Wild Yew
  110. Chemistry:
    –Colorless diterpene alkaloid
    –Low water solubility
    –No ionizable functional groups
    –Solubilize via 50% Cremophor EL (Polyoxyethylated Castor Oil) and 50% dehydrated alcohol
    •Does not alter stability or activity
    •Does increase risk of hypersensitivity rxns
  111. Chemistry:
    –Many closely related alkaloids have been isolated from various Taxus spp.
    –Essential for bioactivity – taxane ring
    •“Northern” half–Ensures proper conformation of essential groups–C-13 ester side chain–C-2’ and C-3’ moieties
    •“Southern” half–Critical to receptor binding
  112. MOA: promotes assembly of mictrotubules from tubulin dimers and stabilizes microtubules to prevent depolymerization of the tubule into the mitotic spindle
    Taxane Alkaloids: Paclitaxel, Docetaxel, Larotaxel, Carbazitaxel
  113. Common Applications:
    Ovarian carcinoma
    – Breast carcinoma
    – Non-small cell and small cell lungcarcinoma
    – Numerous others
    – Drug combinations: Paclitaxel can upregulate thymidinephosphorylase, one activating enzyme of Capecitabine (Xeloda®)
    Paclitaxel & Docetaxel
  114. Special Adverse Effects:
    – Hypersensitivity reactions (20-40%)
    – Sensory: Peripheral neuropathies
    – Cardiac conduction disturbances: Transient sinus bradycardia
  115. Source: a diterpene alkaloid extracted from the needles of the European Yew (Taxus baccata L.)
  116. Chemistry: Semi-synthetic via esterification of the C-13 alcohol of 10-deacetylbaccatin III
    – White (colorless) compound
    – Low water solubility
    – Greater water solubility than paclitaxelbecause of presence of C-10 alcoholinstead of C-10 acetyl ester (paclitaxel)
    – Dissolved in aqueous ethanolic (13%EtOH) Polysorbate 80
  117. Special Adverse Effects:
    – Same as paclitaxel (taxol)
    – Sensory: Peripheral neuropathies
    – Fluid retention (may be significant)
  118. Source– A semi-synthetic taxoid prepared from 10-deacetylbaccatin III
    Larotaxel & Carbazitaxel
  119. Potential Applications:
    – Selected for development because of preclinical evidence of activity against multidrug resistant tumors
    – Poor substrate for the P-glycoprotein drugefflux pump'
    – Phase I and Phase II studies: breastcancer in taxane-resistant patients
    – Phase III studies: advanced pancreatic cancer and advanced bladder cancer
  120. Potential Applications:
    –FDA approves for use in second-line therapy for metastaticprostatic cancer (increased survival by30%) when combined with prednisone/prednisolone in patients who have already been treated with docetaxel
    – Second line option that complements existing therapies
  121. Special Adverse Effect: Same as paclitaxel (taxol)
    – Most common adverse effects leading totermination of therapy were Neutropenia & Renal failure
  122. Resistance to this class of drugs occurs by: Increased expression of the multidrug-resistant gene with elevated P170 glycoprotein levels
    –Enhanced efflux of drug
    –Decreased intracellular drug accumulation
    Taxanes (paclitaxel, docetaxel....)