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72 Cards in this Set
- Front
- Back
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Cell cycle
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G1 Growth occurs as organelles double
S DNA replication occurs as chromosomes duplicate G2 Growth occurs as cell prepares to divide M Mitosis and cytokinesis occurs |
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Cell cycle checkpoints
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Cyclin D/cdk 4, 5, 6
-M phase -when EGFR is upregulated, cycling D is upregulated |
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Classical chemotherapy: cell phase specific vs non cell phase specific
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NON-Cell phase SPECIFIC
-Kill both normal and malignant cells in all phases of cell cycle -Cell kill proportional to dose -Bolus dosing -Alkylating agents, anthracyclines Cell Phase SPECIFIC -Cytotoxic to part of cell cycle in which it is active -Administer via continuous infusion -Mitosis: vinca alkaloids, taxanes -G1: steroids, asparaginase -G2: bleomycin, etoposide, tenoposide -S: antimetabolites, camptothecins |
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Sites of action of cytotoxic agents
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Antimetabolites: DNA synthesis
Alkylating agents: DNA Intercalating agents: DNA transcription, DNA duplication Spindle poisons and microtubule stabilizers: Mitosis |
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Alkylating agents mechanism of action
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One 2-chloroethyl side chain undergoes a 1st order intramolecular cyclization
Result is the release of Cl- and formation of a highly reactive aziridinium ion Binds to DNA resulting in crosslinking or intrastrand -usually on guanine |
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Alkylating agents classes
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Nitrogen mustards
Ethylenimines Alkly sulfonate Nitrosoureas Triazenes Platinum analogues |
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Potential outcomes of alkylating agents
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Template being replicated is misread or mismatched during DNA synthesis
Cross-linking prevents DNA strands from unwinding Single or double-strand breaks in DNA occur DNA molecule ineffective |
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Cyclophosphamide/Ifosfamide clinical uses
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Nitrogen mustards
Cyclophosphamide -Leukemia, lymphomas, solid tumors -Bone marrow transplant (high doses > 2 g/m2) -Treat graft-versus-host-disease -Immunosuppression in nonmalignant diseases: --Rheumatic disorders, lupus, & autoimmune nephritis Ifosfamide -Solid tumors: breast, colon, lung -Testicular cancer -Soft tissue sarcomas |
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Cyclophosphamide/Ifosfamide metabolism
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Given in inactive form
Activated by hepatic metabolism by cytochrome p450 Either inactivated by aldehyde dehydrogenase or converted to acrolein or phosphoramide mustard -acrolein: toxic, ifosfamide causes more acrolein buildup than cyclophosphamide -phosphoramide mustard: cytotoxic, active agent |
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Hemorrhagic cystitis
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Caused by accumulation of ACROLEIN
-Binds to thiol in bladder wall Hematuria, urinary frequency & irritation Prevent with vigorous hydration (≥2 L/day) & MESNA Treat with bladder irrigation, alum irrigation, and other therapies Heme test urine while on therapy |
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MESNA
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Mercaptoethane sodium
Uroprotectant containing sulfhydryl group -Binds to acrolein in the bladder to form a nontoxic compound Not systemically absorbed so does not interfere with cytotoxic activity MESNA is indicated in: -Cyclophosphamide >1 g/m2/dose -Ifosfamide at any dose Effective in PREVENTION only |
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Cyclophosphamide/ifosfamide toxicities
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Cyclophosphamide
-Hemorrhagic cystitis -Delayed Nausea & vomiting -Syndrome of inappropriate anti-diuretic hormone (SIADH) -Pulmonary Ifosfamide -Hemorrhagic cystitis -Neurotoxicity -Renal Fanconi syndrome |
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Platinum agents
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Alkylating
Cisplatin -Renally cleared -Nephrotoxicity – ↓ GFR, electrolyte losses (Mg, K), and renal failure --Prevent with aggressive hydration (NaCl) Carboplatin -Not concentrated in the renal tubules; more efficiently cleared -Dosing based on area under the curve (AUC) --Calvert Equation: Dose = AUC ( GFR + 25 ) (GFR=renal function) Oxaliplatin |
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Platinum analogues uses
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Breast
Lung Testicular Gyn/Onc: cervical and ovarian Colorectal Bladder Lymphoma |
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Platinum analogues toxicities
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Cisplatin
-**Acute/Delayed Nausea/Vomiting -**Nephrotoxicity -Peripheral neuropathy -Neurotoxicity -Ototoxicity Carboplatin -**Myelosuppression - ↓ platelets -Neurotoxicity -Vomiting Oxaliplatin -**Peripheral neuropathy -Myelosuppression |
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Uncommon alkylating agents
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Nitrosoureas
-Carmustine* -Lomustine -Streptozocin -Very liphophilic -Brain tumors Triazenes -Dacarbazine -Temozolomide* -Melanoma, lymphoma, glioma, and sarcoma |
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Common oral alkylating agents
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Chlorambucil (Leukeran)
-Used for the treatment of chronic lymphocytic leukemia Busulfan (Myleran) -Used for treatment of leukemia and transplant -Also available in an IV form (used more for transplant) -Toxicity is decreasing seizure threshold Melphalan (Alkeran) -Used for the treatment of multiple myeloma -8 mg/m2 PO daily day 1-4 repeat every 28 days All three of these medications come as 2 mg tablets (watch dispensing by brand name, avoid wrong drug) |
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Alkylating agents: common toxicities
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Myelosuppression
-Prolonged/delayed myelosuppression nadir Secondary leukemias Infertility Alopecia Nausea/vomiting |
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Topoisomerase inhibitors
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Topoisomerase I inhibitors
-Camptothecins --Irinotecan --Topotecan* Topoisomerase II inhibitors -Anthracyclines --Daunorubicin --Doxorubicin --Idarubicin --Epirubicin -Epipodophyllotoxins --Etoposide* --Teniposide* -Miscellaneous --Mitoxantrone |
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Topoisomerase inhibitors mechanism of actions
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Topo I: 1 nick in DNA
Topo II: 2 nicks in DNA Won't let nicks be resealed |
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Anthracyclines
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Topoisomerase II inhibitors
-Cuts both strands of one DNA double helix can't be resealed Things that end in -rubicin -Daunorubicin -Doxorubicin -Idarubicin -Epirubicin -Miscellanous: --Mitoxantrone |
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Anthracyclines clinical uses
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Doxorubicin/Epirubicin
-Breast cancer --Most active agent -Sarcomas -GI tumors -Lymphoma Daunorubicin/Idarubicin -Leukemia Mitoxantrone -Leukemia -Prostate cancer |
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Anthracyclines toxicities
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**Myelosuppression
**Cardiotoxicity **Extravasation injury -Vesicant -Treat with dexrazoxane (Totect) and cold compress Nausea and vomiting Mucositis Red/orange urine discoloration Radiation recall |
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Anthracyclines cardiotoxicity mechanism of action
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Increased oxygen derived free radicals
Damage lipid proteins and DNA predominantly seen in heard |
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Anthracyclines: cardiotoxicity cumulative dosing
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Doxorubicin cardiotoxicity threshold
-Von Hoff – 7% in patients who receive 550 mg/m2 -Swain data – 26% in patients who receive 550 mg/m2 Patients who receive doses > 350 mg/m2should be treated with caution |
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Anthracyclines: cardiotoxicity classificaiton
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Acute
-Immediate – after a single dose or course of therapy -Decreased contractility, Pericarditis, Myocarditis, Arrhythmia, Elevation of biomarkers Early onset progressive -Within 1 year of therapy with rapid onset and progression -Tachycardia, ventricular dilation, exercise intolerance, pulmonary and venous congestion Late-onset chronic progressive -after 1 year of therapy completion -ventricular dysfunction, conduction disturbances, arrhythmias, CHF |
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Cardiotoxicity prevention
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Dexrazoxane
-Inhibit the iron-dependent free radical formation that can cause myocardial damage Liposomal doxorubicin (Doxil®) -Liposomal delivery system not as readily taken up by cardiac tissue: decreased risk of cardiotoxicity -Used in breast, ovarian cancer |
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Mitoxantrone
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Related to anthracyclines
Does not form free radicals Lifetime dose = 180mg/m2 ↓ cardiotoxicity and extravasation ↓ nausea and vomiting Blue-green urine discoloration |
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Epipodophyllotoxins
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Etoposide (VP-16) & Teniposide (VM-26)
Inhibit topoisomerase II Toxicities -**Myelosuppression -Mucositis (BMT) -Hypotension (diluent) Clinical uses -Etoposide – leukemias, NHL, BMT, small cell lung cancer (SCLC) , ovarian -Teniposide* – ALL, SCLC |
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Camptothecins
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Irinotecan & topotecan
Inhibit topoisomerase I Clinical uses -Ovarian cancer -Lung cancer -Cervical and ovarian cancer -Colorectal cancer |
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Camptothecins toxicities
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Irinotecan:
Severe diarrhea (20%) -Acute (≤ 24 hours) -Atropine Chronic (~11 days) -Loperamide Topotecan: Myelosuppression -Leukopenia -Thrombocytopenia |
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Methotrexate clinical uses
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Clinical uses:
Osteosarcoma Acute Lymphocytic Leukemia Non-Hodgkins and CNS Lymphomas Breast/bladder cancer Non-oncologic uses |
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Methotrexate mechanism of action
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Antimetabolite
Reduced folate analog Taken up intracellularly by cancer & healthy cells Inhibits DHFR: decreases tetrahydrofolate (THF): decrease purine & thymidylate Lack of purines & thymidylate prevents DNA synthesis |
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Leucovorin (folinic acid)
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Required for high dose MTX is lethal unless rescue initiated
Directly converted into tetrahydrofolate -Does not require DHFR Allows resumption of DNA synthesis even in the presence of MTX |
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Methotrexate toxicities and risk factors
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Nephrotoxicity
Myelosuppression GI toxicity Hepatotoxicity Neurotoxicity Dermatitis Death Risk factors: Pre-existing renal dysfunction Urine pH < 7 Concomitant medications Down syndrome Third space fluids -Ascites -Pleural effusions |
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Methotrexate drug interactions
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Sulfonamide: compete with MTX for transport and excretion
PCN: alters urine pH NSAID: decrease renal blood flow, decrease excretion PPI: inhibit H-K ATPase pump in renal tubules |
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Prevention of methotrexate toxicities
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Renal function (CrCl > 60ml/min)
Vigorous hydration and alkalinization of the urine -Administer 3,000 mL/m2/day (125mL/m2/hour) + 30-60 mEq/L -pH > 7 = MTX solubility is pH dependent -Urine specific gravity <=1.01 Avoid interacting medications Leucovorin rescue with high doses (>1g/m^2) Glucarpidase will cleave leucovorin and stop it from working |
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Pemetrexed (alitma)/Pralatrexate (Folotyn)
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Antimetabolites
Pemetrexed: -Multitargeted antifolate -Clinical use: --Malignant pleural mesothelioma --NSCLC -Toxicities: --Cutaneous reaction --FA/B12 supplement required Pralatrexate: -Folic acid analogue -Clinical use: --Relapsed/refractory peripheral T-cell lymphoma -Toxicities: --Mucositis - -platelets/WBC --FA/B12 supplement required |
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Cytarabine overview and mechanism
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Antimetabolite
Arabinose analog of cytosine Phosphorylated to active component within cancer cells Inhibits DNA polymerase |
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Cytarabine clinical uses
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Acute leukemias
-Acute myeloid leukemia -Acute lymphoblastic leukemia -Meningeal leukemia No significant activity against solid tumors |
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Cytarabine toxicities
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Induction state:
(100 mg/M2/day) -**Myelosuppression -Alopecia -Gastrointestinal -Rash—palmer plantar syndrome Consolidation: (1-3 g/M2 q12h) -**Nausea -**CNS toxicity -**Chemical conjunctivitis -**Rash |
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Gemcitabine (Gemzar)
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MOA & structure similar to cytarabine
Effective for solid tumors -Pancreatic cancer -Non-small cell lung cancer -Sarcomas -Bladder cancer Intracellular concentrations 20x > cytarabine |
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Gemcitabine (Gemzar) toxicities
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Myelosuppression
Generalized rashes Fever and flu-like symptoms Peripheral edema Nausea and vomiting-mild NOT Neurotoxic |
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Clofarabine and Nelarabine
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Pyrimidine antagonists
Clofarabine (Clolar) -Relapsed pediatric ALL or relapsed adult AML -AE-skin toxicity-rash to desquamation Nelarabine (Arranon) -T-cell ALL or T-cell lymphoblastic lymphoma -AE-neurotoxicity |
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Fluorouracil: mechanism of aciton
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Fluorinated analog of uracil
Metabolized to FdUMP Inhibits thymidylate synthase Leucovorin synergistically helps fluorouracil by locking in FdUMP and not letting it pop off |
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Fluorouracil: clinical use
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Treatment of solid tumors including breast, colorectal and other GI tumors
Non-oncologic uses: actinic keratoses and noninvasive skin cancers -Cream formulation |
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Capecitabine (Xeloda)
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Oral prodrug of fluorouracil
Metabolized to active component in tumor tissue Use in metastatic colorectal & breast cancer |
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5-FU and capecitabine: toxicities
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**Myelosuppression (bolus)
**Bloody diarrhea and hand foot sydrome (CI) **Mucositis (CI) Dermatologic Ocular Nausea and vomiting (mild) Cardiotoxicity (rare) |
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Purine analogs
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Inhibit de novo purine synthesis
Clinical use: leukemias Mercaptopurine (6-MP) Thioguanine (6-TG) Fludarabine & cladribine -Immunosuppressive T-helpher cells -Prophylactic meds required |
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Vinca alkaloids: MOA
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Mitotic inhibitors
Plant products derived from periwinkle plant Prevent the assembly of tubulin dimers into microtubules Cells accumulate in mitosis |
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Vinblastine, vinorelbine, vincristine uses and toxicities
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Vinca alkaloid, mitotic inhibitor
Vinblastine Uses: -Hodgkin’s disease Lymphomas -Breast -Testicular tumors Toxicity: -Bone marrow suppression, anorexia, nausea,/vomiting & Diarrhea, Alopecia Vinorelbine: Uses : -NSCLC -Breast -Lymphoma -Ovarian Toxicity: -Bone marrow suppression, anorexia, Nausea/ vomiting & Diarrhea, Alopecia Vincristine: Uses: -Childhood leukemias -Childhood tumors-Wilm’s tumor, Neuroblastoma, Hodgkin’s disease Toxicity: -Peripheral neuropathy with Paresthesia, Muscle weakness ***Vincristine has marrow sparing effect All agents are vesicants and fatal if given intrathecally |
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Taxanes: MOA
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Mitotic inhibitor
Promote microtubule assembly Interfere with microtubule disassembly |
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Taxanes: clinical uses
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Ovarian cancer
Breast cancer Melanoma NSCLC Prostate cancer Head and Neck cancer |
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Taxanes: toxicities
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**Myelosuppression
**Mucositis Peripheral neuropathy (cumulative) Alopecia Hypersensitivity reactions* Nausea and vomiting (rare) *premedicate with dexamethasone, H1 and H2 antagonist Paclitaxel -Myalgia -Bradycardia -Cremaphor EL Docetaxel -Fluid retention -Palmar-plantar rash -Polysorbate-80 Cabazitaxel -Myelosuppression -Diarrhea -Fatigue -Ethanol/polysorbate 80 |
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Ixabepilone (Ixempra) MOA
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Mitotic inhibitor
Treatment of patients with metastatic or locally advanced breast cancer: Binds multiple ß-tubulin isoforms, including ßIII-tubulin to inhibit microtubule dynamics -Overexpression of ßIII is associated with in vivo and clinical resistance to taxanes |
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Ixabepilone: adverse events
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Similar to taxane
Neurotoxicity Neutropenia Infusion related reactions |
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Erubulin (Halaven): MOA
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Inhibits formation of mitotic spindles
-Unique mechanism, no cross-resistance with taxanes Indicated for treatment of 3rd-line breast CA |
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Erubulin (Halaven) Adverse effects
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Neutropenia
Alopecia Fatigue Peripheral neuropathy – secondary to previous treatments? |
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Asparaginase: MOA, use, toxicities
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Degrades asparagine found in the serum
Used for leukemia and lymphoma 3 formulations Toxicities: -Allergic reactions -Pancreatitis -fibrinogen |
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Treatment for acute promyelocytic leukemia
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APL
-t(15;17) fuses PML gene with retinoic acid receptor-a (RAR-a) All trans-retinoic acid (ATRA) releases this repression and allows promyelocytes to differentiate Arsenic trioxide (ATO) -QTC prolongation – monitor electrolytes Retinoic acid syndrome (both agents) -Fever, dyspnea, pleural effusion, peripheral edema, hypotension -Treatment: dexamethasone 10 mg IV BID x 3 days |
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Proteasome inhibitors MOA
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Prevent activation of transcription by NFkappabeta
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Bortezomib (Velcade): indications, Toxicities, administration
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proteasome inhibitor
Indications: -Multiple Myeloma -Mantle cell lymphoma Toxicities: -Peripheral neuropathy -Thrombocytopenia -Neutropenia -Fatigue -Weakness -GI effects Intravenous versus subcutaneous administration |
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Carfilzomib (Kyprolis): indicaiton, toxicities
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proteasome inhibitor
Indication: Relapsed/refractory multiple myeloma in patients who have failed therapy with bortezomib and an immunomodulatory agent Toxicities -Cardiac arrest/congestive heart failure -Pulmonary hypertension/dyspnea -Thrombocytopenia |
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Antibiotics (mycin)
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Bleomycin
-Testicular cancer and Hodgkin’s Disease -Watch for pulmonary toxicity and N/V Dactinomycin -Wilms tumor and rhabdomyosarcoma -N/V, decreased counts Mitomycin C -Gastrointestinal tumors -Intravesicularly in bladder cancer |
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Hydroxyurea (hydrea)
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Inhibits ribonucleotide reductase
Used primarily for CML Toxicity: -Myelosuppression Non-oncology indications: Sickle cell disease |
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Immunomodulators
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Thalidomide – for multiple myeloma (MM)
- increased Thromboembolism -Drowsiness/somnolence -Peripheral neuropathies Lenalidomide (Revlimid)-for MDS and MM -Myelosuppression Must have pregnancy test and contraceptive use |
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Histone deacetylators inhibitors MOA
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Histone is a protein important for DNA packing
Acetylation = (HAT) -Control tightness DNA binding Deacetylation (HDAC) -catalyzes remove acetyl groups -Inhibit gene expression Allows the cell to develop normally Cancer cells HDAC allows the cell to grow unregulated HDAI cause accumulation of acetyl groups Induce cell cycle arrest or apoptosis |
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Histone deacetylators inhibitors: clinical use, toxicity
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Clinical Use
-Cutaneous T-cell lymphoma (CTCL) --Cutaneous manifestations in patients --Progressive, persistent or recurrent disease on or following two systemic therapies -Peripheral T-cell lymphoma (PTCL) – romidepsin only Vorinostat – PO only Romidepsin – IV only Toxicities: -Thrombotic events/QTc prolongation -Myelosuppression: decreased platelets/Hgb -GI: nausea/vomiting/diarrhea |
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Hypomethylating agents
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Incorporates into DNA and inhibits transfer of methyl groups
Hypomethylation = leads to cancer cell death Azacitidine (Vidaza) & Decitabine (Dacogen) -Indication: Myelodysplastic syndrome -Decitabine also used in AML Dose limiting toxicity: Myelosuppression |
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Hedgehog pathway inhibitor MOA
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PTCH1 inhibits the release of SMOH receptor
Activation of HH pathway downregulates PTCH1 End result – promotes transcription and DNA replication |
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Vismodegib
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Hedgehog pathway inhibitor
Binds to PTCH1 and blocks release of SMOH receptor to cell wall Used in basal cell carcinomas Adverse effects: -Alopecia -Muscle spasms -Nausea/vomiting -Embryofetal death |
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Corticosteroids, hormonal agents
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Block hormones
Tumors promoted by amount of hormone in body |
