Term
| Goals of cytotoxic chemotherapy |
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Definition
Cure
Extend life
Palliation
Adjuvant therapy: After apparent curative surgery (or radiation) adjuvant chemo is administered to eliminate micrometasteses.
Used in: breast cancer, osteosarcoma, and other tumors |
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Term
| Classes of cytotoxic agents |
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Definition
Alkylating agents: mechlorethamine, cyclophosphamide, dacarbazine, platinum analogs, nitrosureas, etc
Antimetabolites: methotrexate, fluorouracil, mercaptopurine, etc
Plant alkaloids: vincristine, etoposide, irinotecan, paclitaxel, etc
Antibiotics: doxorubicin, bleomycin, etc |
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Term
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Definition
Form reactive electrophiles that covalently bond to nucleophilic sites on nucleic acids and proteins
Favored site for alkylation is the N7 of guanine
Alkylation of DNA is believed to be essential for anticancer effect
Many alkylating agents are bifunctional and can crosslink DNA
All agents cause myelosuppression, toxicity to alimentary tract |
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Term
| Resistance with Alkylating agents |
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Definition
Resistance occurs through:
-Increased repair of DNA
-Decreased uptake of alkylating agent
-Increased synthesis of glutathione (GSH) in cancer cells
Cross resistance among alkylating agents is the rule, but is seen less with nitrosoureas
Many alkylating agents are suspected carcinogens (mechlorethamine & dacarbazine) |
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Term
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Definition
-Undergoes metabolism to reactive components
-May be given orally as well as by injection
-Wide spectrum of antitumor action, especially for solid tumors
-Also used to supress the immune system |
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Term
| Cyclophosphamide degradation- toxicity |
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Definition
Metabolites spontaneously degrade to reactive products in the bladder (acrolein and phosphoramide mustard).
-Consequently cyclophosphamide causes hemorrhagic cystitis
MESNA can be administered to prevent this
Ifosfamide is a very similar drug with a higher incidence of hemorrhagic cystitis. Mesna MUST be given with ifosfamide
-Patients receiving these drugs may, years later, develop bladder cancer |
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Term
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Definition
-Used in the tx of testicular cancer and other solid tumors
-Early on, low doses were used because of limiting toxicity: renal damage & N/V
-Now, mannitol + hydration + 5HT3 blockers protect kidney and supress N&V and higher doses can be used.
-Myelosuppression and neurotoxocity are problematic with these high doses |
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Term
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Definition
| Associated with less N/V but more myelosuppression than cisplatin |
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Term
| Cell cycle specificity of anticancer chemotherapy |
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Definition
Agents are either cell cycle specific or cell cycle non-specific
-Cell cycle specific agents are toxic to cells at a specific stage of the cell cycle while cell cycle non-specific are not. Non specific agents can kill in the G0 stage.
Non-specific drugs are even more toxic than specific drugs during cell division. |
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Term
| Cell cycle non-specific agents |
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Definition
All alkylating agents
Antibiotics |
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Term
| Cell cycle specific drugs |
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Definition
S phase: antimetabolites, hydroxyurea
M phase: vinca alkaloids, paclitaxel
G1 phase: asparaginase |
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Term
| Utility of cell cycle specificity |
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Definition
Cell cycle specific drugs are not active versus resting cells, so it makes sense to use a non-specific agent first to "recruit" cells into division
-If L-asparaginase is given before the methotrexate the cytotoxicity of methotrexate is lessened.
-Give methotrexate first |
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Term
| Order of phases in cell cycle |
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Definition
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Term
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Definition
-Similar structure to folic acid
-It is a competitive inhibitor of dihydrofolate reductase (DHFR). Prevents the activation of folic acid to tetrahydrofolate
-Thus deprives cells of a methyl donating molecule.
-N5,N10 methylene FH4 is a cofactor in thymidylate synthase, which converts dUMP to dTMP |
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Term
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Definition
-A form of THF that is available as a drug and can reverse or prevent methotrexate toxicity.
-Sometimes a lethal dose of MTX is given and is followed by a rescue dose of leucovorin
-It potentiates the activity of 5-FU, so it can be used to potentiate the effects. Binding of leucovorin enhances the ability of fluorouracil to bind/inhibit thymidylate synthase.
-Effects of leucovorin on MTX are exactly the opposite of its effects on 5-FU |
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Term
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Definition
| Folic acid analog which inhibits thymidylate synthase more than dihydrofolate reductase |
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Term
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Definition
-Used in a wide variety of solid tumors
-Dose limiting effect: damage to epithelium of the alimentary canal
-Metabolism by gut dihydropurimidine dehydrogenase-- low bioavailability
Capecitabine: an orally active fluorouracil prodrug
MOA: fluorouracil is converted to d-fUMP which inhibits thymidylate synthase.
d-fUTP and fUTP can also be incorporated into DNA or RNA |
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Term
| MOA of fluorouracil/capecitabine |
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Definition
-Readily absorbed from the GI tract and rapidly converted in the liver by coarboxylesterase to 5'-deoxy-5-fluorocytidine
-Cytidine deaminase, ubiquitous enzyme, converts 5'-deoxy-5-fluorocytidine to 5-deoxy-5-fluorouracil which is converted to nucleotides to exert anticancer effect
-Cytidine deaminase and thymidine phosphorylase are present in tumor cells and there are reports that activity of latter is elevated in tumor cells
-Thymidine phosphorylase hydrolyzes 5'-deoxy-5-flurouracil to produce free 5-fluorouracil (5-FU) which is converted to nucleotides to exert anticancer effect.
-Cytidine deaminase and thymidine phophorylase are present in tumor cells and there are reports that activity of latter is elevated in tumors. |
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Term
| Dihydropyrimidine dehydrogenase (DPD) |
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Definition
-5FU is inactivated through DPD
-Individuals deficient in DPD experience severe, even fatal toxicity if treated with 5-FU or derivatives |
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Term
| Directed therapy of cancer |
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Definition
Drugs are targeted at molecular targets of cancer cells, so they generally do not show the traditional toxicity of cytotoxic cancer chemotherapy drugs.
-Associated with different kinds of toxicity |
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Term
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Definition
All the antibody in a monoclonal antibody is identical.
-Produced by a clone of the same antibody producing cell.
-End with "mab"
-Administered IV
-Bind to very specific antigens, designed to specifically target cancer antigens
--cancer cells express proteins (and oncogene products) that are not frequently expressed in normal cells
-Naked monoclonal antibodies have anticancer action.
-Monoclonal conjugates are monoclonal antibodies that are attached to a toxic substance: could be radioactive or cytotoxic |
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Term
| Mechanisms of antibody-mediated anti-cancer effects |
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Definition
-Delivering a radioactive compound or toxic compound to the tumor
-Interfering with the function of a key protein on the tumor
-Provoking cell-mediated cytotoxicity
Two or more mechanisms may operate simultaneously |
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Term
| Cell-mediated cytotoxicity |
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Definition
-Cell overexpresses CD20, which makes cancer cell different from other cells in the body
-A monoclonal antibody drug is given that binds to this surface protein.
-Binding induces macrophages and other cells of the immune system to attack and destroy the cell |
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Term
| Complement dependent cytotoxicity |
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Definition
-Series of proteins that undergo a chain reaction in which one compound activates the next
-Active components form pores in the cell membrane, causing cell lysis and destroying integrity of the cell membrane
-Binding to the receptors that are overexpressed on cancer cells can induce conformational changes----> lysis |
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Term
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Definition
-First monoclonal antibody approved for cancer
-Binds to CD20 antigen on B-cell precursors and mature B cells
-Provokes antibody-dependent and complement mediated cytotoxicity.
-Interference with CD20 function may kill cells via apoptosis
Indicated for tx of CD20 positive non-Hodgkin lymphomas, with combined chemotherapy
-Produces prolonged suppression of B-lymphocytes, with diminished serum antibodies & increased risk of infection
-Infusion rxns are common
-Delayed lung damage happens occasionally
-Severe bone marrow depression & pancytopenia |
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Term
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Definition
-Monoclonal antibody directed against surface protein HER2/neu receptor
-Used in breast cancers that overexpress HER2
-HER2/neu is the product of an oncogene and its inhibition may contribute to trastuzumab's action by decreasing angiogenesis and decreasing proliferation
Indicated in the tx of metastatic breast cancer with HER2 overexpression
-Sole agent after failure of chemotherapy
-In combo with chemo as front-line therapy
-In combo with chemo as adjuvant therapy
-With paclitaxel for neoadjuvant (preoperative) therapy |
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Term
| Trastuzumab: adverse effects |
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Definition
Infusion related reactions are common, hypersensitivity
Cardiotoxicity including arrhythmias and heart failure (caution in elderly or debilitated). Combination with anthracycline increases risk |
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Term
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Definition
-A humanized monoclonal antibody against the CD52 protein which is on the surface of both B and T lymphocytes
-Used for refractory chronic lymphocytic leukemia, T-cell lymphomas
-Causes infusion reactions and prolonged depletion of lymphocytes, perhaps very prolonged T cell depletion |
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Term
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Definition
-Anti-angiogenesis agent used in colon cancer
-It is humanized monoclonal antibody against vascular endothelial growth factor (VEGF)
-Avoid where bleeding poses a threat, including post op patients
-Good because cancers usually develop their own blood supply which enables them to grow
-Drug is targeted at growth factor, not receptor on cancer cell |
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Term
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Definition
-A human-mouse chimeric monoclonal antibody against epidermal growth factor receptor (EGFR) on the surface of many cancer cells
-Rashes are common with therapies directed against EGFR and correlate with increased response to therapy. Rash clears after a few days |
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Term
| Identifying Monoclonal antibody drugs |
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Definition
Omab: Mouse
-Problem in humans, antigenicity resulting in allergic reaction. Antibody against antibody
Imab: chimeric
-Mouse and human antibody
Umab: Humanized
-Antibodies that have virtually no mouse component |
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Term
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Definition
-A mouse antibody directed against the CD20 antigen on white cells of the B line
-Ibritumomab is the antibody while tiuxetan is an attached chelating molecule
-y90 (yttrium-90) is chelated to the molecule which delivers beta particles to the targeted lymphoma cells. y90 has a short half-life and must be made up shortly before use.
-Used to treat indolent non-Hodgkin lymphomas
-Causes profound bone marrow suppression and allergic reactions.
-Related drugs: rituximab and tositumomab (Bexxar) |
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Term
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Definition
Humanized antibody specific for CD33 marker on surface of melocytes. Present in large majority of acute myelocytic leukemias (AMLs)
-Linked with semisynthetic anticancer antibiotic ozogamicin
-Causes profound bone marrow suppression, hepatotoxicity and hypersensitivity
-Used to treat AML |
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Term
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Definition
-Not an antibody but similar mechanism as the conjugated monoclonal antibodies
-It is a fusion protein that combines recombinant interelukin 2 (IL-2) with diphtheria toxin
-Specifically binds to a transient high affinity IL-2 receptor (CD25, CD122) which internalizes the molecule
-This normally transient receptor is permanently expressed on malignantly transformed lymphocytes
Approved for recurrent/refractory cutaneous T-cell lymphomas
-Toxicities include flu-like reactions, hypersensitivity and a vascular leak syndrome.
-Lymphopenia with increased risk of infections occurs and depression of other formed elements can occur.
-Aldesleukin is IL-2, used in treating renal cancer |
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Term
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Definition
-Blood mononuclear cells are harvested 3 days before infusion. They are treated with a recombinant fusion protein made up of prostatic acid phosphatase (PA) fused to granulocyte-macrophage colony stimulating factor (GM-CSF)
-Idea is that T-cells infused will attack cancer cells with PAP on the surface.
-EXPENSIVE, and only add a few months to life
-Used as a treatment vaccine for prostate cancer |
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Term
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Definition
-Enzymes that phosphorylate the -OH of tyrosine residues.
-Uncontrolled cell growth is often stimulated by tyrosine kinases.
-Involved in signal transduction of many growth factors
-Up-regulation of TK activity is a mechanism by which many oncogenes and tumor suppressor genes work
-Activation of tyrosine kinase can phosphorylate other proteins and cause multiple effects:
-Proliferation, invasion, inhibition of apoptosis, metastasis, angiogenesis
Two major types of tyrosine kinases:
-Receptor linked: have an external component on the cell membrane
-Non-receptor linked: within the cytoplasm but are usually anchored to the cell membrane internally |
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Term
| Small molecule inhibitors of tyrosine kinase |
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Definition
-In theory, inhibition of tyrosine kinase should reverse the cellular processes associated with cancer.
-Drugs have unpredictable toxicity
-cABL (Philadelphia chromosome) leads to excess TK activity and contributes to chronic myelocytic leukemia
-platelet derived growth factor: Dimerization of the receptor occurs, then the products of the activated receptor go on to activate the non-receptor TK. |
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Term
| Targets for inhibition of tyrosine kinases |
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Definition
-Ligand
-Receptor
-Catalytic component of TK's
Drugs:
-Bevacizumab- VEGF
-Cetuximab- EGFR
-Trastuzumab- HER2 |
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Term
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Definition
-Inhibits tyrosine kinase
-Effective in CML (genetic abnormality was consistently found in CML).
-Imatinib inhibits TK that is found almost exclusively in the cancer cells
-Purposely designed to inhibit tyrosine kinase. Inhibits the TK of the bcr-abl fusion protein of the Phil chromosome.
-Dasatinib & nilotinib are other bcr-abl inase inhibitors that may be useful after resistance to imatinib develops.
-Resistance is due to modification of the ABL kinase or sometimes amplification of the fusion protein |
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Term
| Cell Surface Receptor Blockers of TK |
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Definition
| Cetuximab and trastuzumab |
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Term
| Ligand-binding TK inhibitor |
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Definition
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Term
| Intracellular inhibitors of TK |
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Definition
-End in "nib"
-Orally active
-Imitinib (Gleevac)
-Gefitinib (Iressa)
-Erlotinib (Tarceva)
-Lapatinib (Tykerb)
-Sorafenib (Nexavar)
-Sunitinib (Sutent) |
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Term
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Definition
-Associated with increased risk of arterial thrombotic disease
-Attributed to inhibition of VEGF associated TK |
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Term
| Chronic myelogenous leukemia (CML) |
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Definition
-First cancer to clearly show a genetic defect (Nearly 100% of cases have Phil. chromosome)
-Associated with short survival
-Occurs in all age groups
3 Stages:
-Chronic- asymptomatic patients. Detected by abnormal blood work (high WBC). Can persist for years. This is when imatinib is most effective
-Accelerated- characterized by failing platelet counts, increasing splenomegaly, increased blasts in marrow
-Blast crisis- blood cells appear like acute leukemic blast forms. Rapid progression and short survival times. Imatinib is least effective here. |
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Term
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Definition
-Also inhibits PDGF-R (platelet derived growth factor receptor) TK
--potential use in some solid tumors, myeloproliferative disease, medulloblastoma (brain tumor)
-Inhibits the Kit tyrosine kinase receptor that is abundant in GI tumors (GI stromal tumors)
Adverse effects:
-Edema (can cause pericardial or pleural effusion)
-Skin rash
-In leukemia: thrombocytopenia and neutropenia
-Muscle cramps and pain
-Possible myocardial damage leading to heart failure (maybe related to mitochondrial damage, cardiac cell muscle apoptosis) |
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Term
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Definition
-Inhibitor of epidermal growth factor type 1 (ErbB1 or HER1), which is overexpressed in many tumors
-Approved for non-small cell lung cancer (NSCLC) and may find more indications in the future. Response rate has been modest
-Resistance due to mutation in the target TK
Adverse effects:
-GI effects- diarrhea and nausea
-Rashes
-Rare, potentially fatal lung disease |
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Term
Lapatinib (Tykerb)
Erlotinib (Tarceva) |
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Definition
-A dual inhibitor of epidermal growth factor and HER2 TK
-Approved in treatment in combination with capecitabine, of unresponsive metastatic breast cancer that is HER2-positive
Adverse effects:
-diarrhea, nausea, hand-foot syndrome, rash, some cardiotoxicity (less than trastuzumab)
Erotinib is an epidermal growth factor receptor kinase inhibitor that has been used in NSCLC and pancreatic cancer |
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Term
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Definition
-Inhibitors of various TK's
-Important anti cancer effect: inhibition of TK of the vascular endothelial growth factor receptor
Adverse effects:
-Hypertension and heart failure
-Bleeding, rashes, and hand & foot syndrome are also associated |
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Term
| Sunitinib plus bevacizumab |
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Definition
| -Used to create dual inhibition of angiogenesis -Not very effective because the synergy seen was most with toxicity, not beneficial treatment synergy |
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Term
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Definition
| -Small dipeptide containing boron -Proteosome inhibitor released for multiple myeloma -Proteosomes are large complexes in cytoplasm which function to degrade proteins that have been tagged by polyubiquination -Bortezomib may inhibit destruction of various proteins that are protective against cancer -Administered via IV bolus -Potentiates the effects of traditional cytotoxic chemotherapy Adverse effects: -Peripheral neuropathy, bone marrow suppression, and hypotension |
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Term
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Definition
-Diff agents change the phenotype of cancer cells. They no longer look like cancer cells, but differentiate into mature cells
-APML has a characteristic 15:17 chromosome translocation involving the RAR-alpha (retinoic acid receptor) |
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Term
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Definition
-An all-trans retinoic acid (ATRA)
-Oral tretinoin can induce remission in APML and is used in combo with anthracycline antibiotics in potential curative therapy
-Fixes the chromosomal translocation that was present in cancer cells
-Remission is short-lived
-Combo therapy is very effective in this form of cancer
MOA: fusion protein produced by the chromosomal translocation in APML has decreased affinity for retinoid and inhibits the function of transcription factors which promote differentiation of myeloid elements. High dose tretinoin removes this inhibition and promotes differentiation
-Doesn't kill tumor cells |
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Term
| Addtional Tretinoin info & related drugs |
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Definition
-Highly toxic
-Retinoic acid syndrome: fever, dyspnea, edema, pulmonary infiltrates and pleural or pericardial effusions can be fatal
-Prompt treatment with oral steroids with this s/e
-Retinoids are teratogenic, associated with fetal malformations
Related Drugs:
-Alitretinoin, used topically in Kaposi's sarcoma.
-Bexarotene is a synthetic compound that acts as agonist at retinoid RXR receptor used orally (and topically) for cutaneous T-cell lymphoma |
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Term
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Definition
-Given IV in the treatment of APML
-Induces differentiation
-Well tolerated, but can occasionally induce a retinoic acid syndrome, skin changes, and QT prolongation in EKG |
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Term
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Definition
-Potent anti-multiple myeloma agent
-Numerous potential anticancer actions
-Diminishes the release of cytokines related to angiogenesis like VEGF and TNF-alpha
-Inhibits factors like NF-kB and Bcl-2 that have anti-apoptotic effects
-Increase T-cell production of cytokines like IL-2 and interferon-gamma that potentiate natural killer cells
Adverse effects:
-Sedation, peripheral neuropathy and congenital defects
Lenalidomide- closely related & shares anticancer effects but lacks teratogenicity |
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Term
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Definition
-A slightly modified form of IL-2, a cytokine that stimulates T-cell growth and activity
-Anticancer activity is due to promotion of T-cell attack.
-Used IV in treating metastatic renal cancer, AML, & non-Hodgkin's Lymphoma
-Substantial toxicity: infusion rxns, hypotension, arrythmias, edema, nausea, etc |
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Term
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Definition
-A poly ADP-ribose polymerase 1 (PARP1) inhibitor
-PARP1 is most abundant of a family of enzymes that repair DNA single-strand breaks
-Used in tumors with double loss of tumor suppressor BRCA1 or BRCA2
Theory: These tumor cells, but not normal cells, have impaired capacity for DNA repair. Thus they will be selectively susceptible to PARP1 inhibition. Inhibition of DNA repair will be more damaging to cells that already have compromised DNA repair.
-Substantial anticancer effect in colorectal, prostate, and other cancers as well as breast cancer in persons with mutations of BRCA1 or 2 |
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Term
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Definition
-Deoxycytidine analogs first synthesized as antimetabolites, inhibit DNA methyltransferase.
-Decreased methylation of DNA imparts anticancer action |
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Term
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Definition
| -Potent inhibitor of histone deacetylase that is employed orally in the treatment of cutaneous T cell lymphoma |
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Term
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Definition
-Diminishes cardiotoxicty of anthracycline antibiotics like doxorubicin
-Generation of reactive oxygen spp is responsible for this side effect
-Transition metal ions (like Fe in cardiac cells) enhance the effect of some reactive ooxygen spp
-Dexrazoxane is converted intracellularly to a chelating agent which lowers free Fe in cardiac cells.
-May increase bone marrow depression. |
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Term
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Definition
-Dephosphorylated after IV administration to produce a sulfhydryl compound that can afford some protection against a wide array of cytotoxic cancer drug effects:
-bone marrow depression, nephro/neurotoxicity
-Hypotension & skin rashes occur
-Antagonize anticancer effect?? |
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Term
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Definition
-Recombinant human keratinocyte growth factor.
-Enhanced stability due to 23 removed amino acids
-Minimizes the mucositis of the mouth and GI tract caused by chemo or radiation.
-Given IV
-Causes thick tongue and adverse dermatologic effects |
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Term
| Prevention of infections, anemia, & bleeding with factors that stimulate bone marrow activity |
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Definition
Filgrastin/pegfilgrastim: hGCSF to combat neutropenia
Epoeitin/Darbopoeitin: recombinant human erythropoeitin for anemia. Darb has longer DOA. Possible s/e: Pure red cell aplasia
Oprelvekin: recombinant IL-11 to stimulate platelet formation and combat thrombocytopenia
Adverse effects of these drugs:
-Fluid retention, bone pain, increased viscosity, cardiac and renal problems, and possibly increased risk of death if used overaggressively. |
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Term
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Definition
5HT3 antagonists: ondansetron, granisetron
Corticosteroids: dexamethasone
Dopamine D2 antagonists: haloperidol
Substance P receptor antagonist: aprepitant |
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Term
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Definition
-Only the amino-bisphosphonates should be used in cancer
-Pamidronate, ibandronate, and zoledronate
-Inhibit osteoclast activity
-Diminish pain of bony metastasis
-Aminobisphosphonates have anticancer & antiangiogenic effects |
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Term
| Stem cell transplant: Chemotherapeutic agents used in conditioning regimens |
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Definition
-Sometimes combined with total body irradiation
-Cyclophosphamide
-Busulfan
-Melphalan
-Fludarabine |
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Term
| Drugs are used after stem cell transplants to treat acute effects or long-term effects |
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Definition
-Anti-rejection drugs (cyclosporin, corticosteroids)- for graft v host disease
-Colong stimulating factors (filgrastim, epoietin, oprelvekin)
-Antiinfectives
-Others |
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Term
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Definition
Common & life-threatening side effect of stem cell/bone marrow transplant.
Occurs when transplanted stem cells recognize the recipient's body as foreign, and "reject" it.
-Less common with cord blood transplant and autologous stem cell transplant |
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Term
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Definition
-Good thing
-Stem cell transplant produces cells that attack residual cancer cells. |
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