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69 Cards in this Set
- Front
- Back
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What is the mechanism of action of Cetuximab and what are some of its toxicities?
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MOA: binds to EGFR (ErbB-1/HER1), and in effect competitively inhibits EGF/TGF-α binding, thus blocking signaling for tumor cell growth, angiogenesis, and metastasis; Toxicities: Acneform rash (like Erlotinib), infusion reactions
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What is the difference between Filgrastim and Pegfilgrastim and what drug interactions are associated with them?
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Pegfilgrastim is pegylated, thus substantially increasing its half-life (since it cannot be filtered out at the glomerulus); Both drugs should not be used concomitantly with cycle-specific chemotherapy (e.g. with 5-FU) since it can worsen myelosuppression
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What is the mechanism of action of Sargramostim and what are its toxicities?
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MOA: since it is a GM-CSF, it has the same MOA as Filgrastim; Toxicities: also similar to Filgrastim, but includes myalgias
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What is Oprelvekin and what is its mechanism of action?
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IL-11; MOA: stimulates multiple stages of megakaryopoiesis and thrombopoiesis
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What two drugs are interleukins and how do they differ?
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Aldesleukin (IL-2): stimulates the immune system, severe toxicities associated with it (e.g. hypotension), only used as a last resort; Denileukin (fusion protein of diphtheria toxin fragments and IL-2): targets delivery of toxin to cells expressing an IL-2 receptor, used to destroy cells in some leukemias/lymphomas
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What is Alpha interferon used for and what toxicities are associated with it?
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Leukemias, lymphomas, melanomas, myelomas – toxicities: flu-like symptoms, n/v, weight loss
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What are the biologic effects of interferons?
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Antiproliferative; Immunomodulatory; Differentiation (monocytes --> macrophages); Antigen expression (increased Ig expression on lymphocytes); Oncogene expression (reduced)
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What is the primary site of metabolism for recombinant drugs and why?
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Kidney – since they are small, the drugs can leak through the glomerulus; however, when they are reabsorbed in the nephron, they are degraded by local proteases
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How does the effectiveness of treatment compare when looking at biologic response modifiers, between continuous SC infusion and bolus IV?
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Continuous SC is far more effective than bolus IV
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What are the nonspecific immunostimulants?
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BCG; Levamisole
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What problems are associated with MoAb use?
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Cross-reactivity with normal tissues; Antigenic modulation (receptor internalization); Development of anti-mouse antibodies by patient (can only give one dose); Tumor heterogeneity in antigen expression; Tumor lacks adequate blood supply; Lack of direct toxicity; Lack of host accessory effectors
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What is the nomenclature used for MoAb?
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Common suffix is “mab”; Antibody source: u = human, o = murine; xi = chimeric
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What are compounds called that modify the host’s biologic response to tumor cells?
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Biologic Response Modifiers
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What is particular about the half-life of monoclonal antibodies (MoAb) and what is the most important organ for clearance?
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Half-life is long; Liver and reticuloendothelial system are most important organs for clearance
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What two drugs are interleukins and how do they differ?
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Aldesleukin (IL-2): stimulates the immune system, severe toxicities associated with it (e.g. hypotension), only used as a last resort; Denileukin (fusion protein of diphtheria toxin fragments and IL-2): targets delivery of toxin to cells expressing an IL-2 receptor, used to destroy cells in some leukemias/lymphomas
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What is Alpha interferon used for and what toxicities are associated with it?
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Leukemias, lymphomas, melanomas, myelomas – toxicities: flu-like symptoms, n/v, weight loss
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What are the biologic effects of interferons?
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Antiproliferative; Immunomodulatory; Differentiation (monocytes --> macrophages); Antigen expression (increased Ig expression on lymphocytes); Oncogene expression (reduced)
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What is the primary site of metabolism for recombinant drugs and why?
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Kidney – since they are small, the drugs can leak through the glomerulus; however, when they are reabsorbed in the nephron, they are degraded by local proteases
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How does the effectiveness of treatment compare when looking at biologic response modifiers, between continuous SC infusion and bolus IV?
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Continuous SC is far more effective than bolus IV
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What are the nonspecific immunostimulants?
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BCG; Levamisole
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What is the mechanism of action of Trastuzumab and what are some of its toxicities?
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MOA: binds to HER2 receptor leading to cell cycle arrest, and acts as a mediator of antibody-dependent cell-mediated cytotoxicity via natural killer cells and monocytes; Toxicity: hypersensitivity, CHF (especially in combination with Doxorubicin – signs may be delayed)
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What is the mechanism of action of Filgrastim and Pegfilgrastim and what are some of their toxicities?
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MOA: they are G-CSF and thus stimulate multiple stages of neutrophil production as well as increase the activity of individual neutrophils; Toxicity: bone pain, hyperuricemia
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What are the established roles of neutrophil-related growth factors?
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Prevention (not treatment) of neutropenic fever following “standard-dose” chemotherapy; Acceleration of hematopoietic recovery following “high-dose” chemotherapy; Generation of autologous peripheral blood progenitor cells; Treatment of chronic neutropenic states
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What are the indications for EPO?
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Anemia secondary to renal failure, malignancy, or chemotherapy
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Besides causing hematopoiesis, what negative side-effects are associated with EPO?
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Cancer-related angiogenesis (via VEGF), promotion of cancer cell migration; also hypertension, thrombotic events, and seizures
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What is the mechanism of action of Tositumomab?
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MOA: it is murine IgG conjugated with Iodine131, which binds to CD20 on B-cells, leading to complement-dependent toxicity, antibody-dependent cellular toxicity, and direct toxicity of radioactivity (to the bound cell and adjacent cells)
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What is the mechanism of action of Gemtuzumab and what are some of its toxicities?
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MOA: it is humanized IgG conjugated with the toxin calicheamicin, which becomes internalized after CD33 binding on leukemic cells (causes dsDNA breaks); Toxicities: myelosuppression
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What is the mechanism of action of Bevacizumab and what are some of its toxicities?
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MOA: binds to VEGF, thus inhibiting tumor-related angiogenesis; Toxicities: hypertension, proteinuria, problematic wound healing (since it inhibits angiogenesis)
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What is the mechanism of action of Rituximab and what are some of its toxicities?
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MOA: binds to CD20 on B-cells (CD20 regulates cell cycle), and causes B cell lysis; Toxicities: Infusion reactions, risk of acute death – Rituximab is used for B-cell non-Hodgkin’s lymphoma
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How are Paclitaxel and Docetaxel metabolized?
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By CYP3A4 and 28C (Paclitaxel only) – they are easily cleared from the CNS thus reducing the effects there; this can lead to increased relapse rates in the brain
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What is the mechanism of action of Paclitaxel and Docetaxel?
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Promotes microtubule assembly and then inhibits depolymerization, thus stabilizing the microtubules in their non-functional state
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What important toxicities and drug interactions are associated with Irinotecan?
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Myelosuppression; n/v; Diarrhea: early (treated with atropine), late (treated with loperimide) – Drug interactions: CYP3A4 inducers/inhibitors
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What is the mechanism of action of Vincristine and what is its half-life?
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Binds tubulin, thus inhibiting microtubule formation (i.e. M phase specific = mitotic arrest) – it’s half-life is long (>20 hrs)
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What are the mitotic inhibitors used in chemotherapy?
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Vincristine, Vinblastine, Vinorelbine, Paclitaxel, Docetaxel, Ixabepilone
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What is the mechanism of action of Temsirolimus?
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It binds to FKBP-12 and inhibits mTOR (like Sirolimus) --> this leads to growth arrest
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What is the mechanism of action of Tamoxifen and what are its important toxicities?
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Competitive estrogen antagonist (mostly G2 specific) – Toxicities: menopausal symptoms, thromboembolism, flare reaction, ocular/endometrial/uterine cancer
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What are the estrogen receptor modulators used in chemotherapy?
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Fulvestrant, Tamoxifen, Toremifene
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What are the two subclassifications of anti-estrogen therapies and what characterizes each?
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Receptor modulators: used pre- or post-menopausal, toxicities include blood clots / uterine cancer;
Aromatase inhibitors: used post-menopausal, toxicities include osteoporosis / fractures |
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What pharmacological class is Vorinostat and what is its mechanism of action?
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Histone deacetylase inhibitor – MOA: inhibits HDAC1,2,3,6 which catalyze removal of acetyl groups from histones and transcription factors --> cell cycle arrest and/or apoptosis
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What pharmacological class is Bortezomib and what is its mechanism of action?
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It is a proteasome inhibitor – MOA: reversible inhibitor of ubiquitin proteasome pathway
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What is the pharmacologic class of Arsenic Trioxide and Tretinoin
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They are differentiating agents
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What two signal transduction inhibitors are competitive inhibitors of ATP on the tyrosine kinase Bcr-Abl and how do they differ?
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Imatinib and Dasatinib – Dasatinib has activity in Imatinib-resistant cell lines
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Which signal transduction inhibitors are used for renal cell cancer and what is characteristic of them?
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Sorafenib and Sunitinib – both are multi-kinase inhibitors causing inhibition of proliferation and antiangiogenesis; since they affect multiple tyrosine kinase inhibitors, they have more extensive toxicities associated with them
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Which signal transduction inhibitors are associated with the EGFR/ErbB-1/ HER1 tyrosine kinases and what differentiates between them?
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Erlotinib and Lapatinib – Erlotinib: causes cell cycle arrest and inhibition of angiogenesis, and is associated with a rash (no rash = no efficacy); Lapatinib has a dual action on ErbB-1 and ErbB-2, making it useful in HER-2 positive breast cancer
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What is the mechanism of action of Leuprolide?
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It is a GnRH agonist --> causes an initial surge of LH/FSH from the pituitary, temporarily increasing the levels of testosterone (~ 1 week) --> ultimately secretion of LH/FSH is decreased by continuous receptor stimulation – used to treat prostate cancer (also breast/ovarian cancer)
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What important toxicities are associated with Leuprolide?
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Hot flashes, reduced libido, impotence, gynecomastia
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What is particular about the pharmacokinetics of Tamoxifen?
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It is metabolized by several CYP450 enzymes (3A, 2C, 2D6); however, in order to achieve maximal efficacy, Tamoxifen must be metabolized by CYP2D6 to highly active metabolites; since ~10% of Caucasians do not have CYP2D6, this can cause problems; Inhibitors of CYP2D6 should also be avoided
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What are the androgen receptor antagonists, used in chemotherapy and for what specific cancer are they important treatment options?
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Bicalutamide, Flutamide – used in prostate cancer
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What is the mechanism of action of Anastrozole and what toxicities are associated with it?
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MOA: blocks aromatase conversion of androgens to estrogens in peripheral tissues; Toxicities: menopausal symptoms, vaginal dryness/bleeding, GI effects, osteoporosis
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What are the aromatase inhibitors used in chemotherapy?
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Aminoglutethimide, Anastrozole, Letrozole, Exemestane
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What problems are associated with MoAb use?
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Cross-reactivity with normal tissues; Antigenic modulation (receptor internalization); Development of anti-mouse antibodies by patient (can only give one dose); Tumor heterogeneity in antigen expression; Tumor lacks adequate blood supply; Lack of direct toxicity; Lack of host accessory effectors
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What is the nomenclature used for MoAb?
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Common suffix is “mab”; Antibody source: u = human, o = murine; xi = chimeric
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What are compounds called that modify the host’s biologic response to tumor cells?
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Biologic Response Modifiers
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What is particular about the half-life of monoclonal antibodies (MoAb) and what is the most important organ for clearance?
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Half-life is long; Liver and reticuloendothelial system are most important organs for clearance
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What important pharmacokinetics are associated with Doxorubicin?
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It has a large volume of distribution; Elimination is via bile, so bilirubin levels must be checked
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What is the most common antitumor antibiotic and what is its mechanism of action?
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Doxorubicin; MOA: free radical formation, topoisomerase II interaction (!), DNA intercalation
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What are the mechanisms of action of 5-Fluorouracil (5-FU)?
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Inhibition of thymidylate synthase (= decreased thymidine); Incorporation into RNA and DNA leading to apoptosis – some S phase specificity
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What are important toxicities associated with 5-FU and what drug is used in association with 5-FU?
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Toxicities (continuous infusion): mucositis, diarrhea, hand-and-foot syndrome (paresthesias, redness --> pain --> peeling --> resolution); Toxicities (daily bolus): myelosuppression; Drug interactions: Leucovorin (folinic acid) stabilizes/prolongs binding of 5-FU to thymidylate synthase
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What compound causes deactivation of 5-FU?
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Dihydropyrimidine dehydrogenase (DPD); 5-FU has a short half-life (min.) – DPD deficiency often results in lethal toxicity
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What are the antitumor antibiotics?
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Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone, Actinomycin D, Bleomycin
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What is the active metabolite of Irinotecan and how is it excreted?
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Irinotecan is converted by carboxyesterases to SN-38 (100-1000x more active); SN-38 is glucoronidated and excreted in the bile; CYP3A4 also metabolizes Irinotecan, but forms inactive metabolites
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What is the mechanism of action of Irinotecan?
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Stabilization of a ternary complex between topoisomerase I and dsDNA, inducing single strand breaks, thus preventing cells from entering mitosis (G2 arrest)
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What are the topoisomerase I inhibitors?
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Irinotecan, Topotecan
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What toxicities are found with Doxorubicin?
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Cardiac problems: acute arrhythmias and chronic CHF (keep lifetime dose <550 mg/m2); Vesicant; Radiosensitizer; May make patient’s fluids/tissues red
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What important toxicities are associated with Vincristine?
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Neuropathies: decreased DTR --> paresthesias --> autonomic dysfunction; SIADH; Photosensitivity; NOT myelosuppression (sets it apart) – If accidentally given intrathecal, it is almost always lethal
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What is characteristic of the metabolism of signal transduction inhibitors?
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They are all metabolized by CYP3A4
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What are the signal transduction inhibitors used in chemotherapy?
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Dasatinib, Erlotinib, Imatinib, Lapatinib, Sorafenib, Sunitinib, Temsirolimus
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What sets Ixabepilone apart from Paclitaxel and Docetaxel?
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Although it has a similar MOA as Paclitaxel/Docetaxel, it is less susceptible to MDR/P-gp and may therefore work on vinca/taxane/anthracycline resistant cells
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What important toxicities are associated with Paclitaxel and Docetaxel, respectively?
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Paclitaxel: acute anaphylaxis, myelosuppression, peripheral neuropathy; Docetaxel: myelosuppression, peripheral neuropathy, fluid retention
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