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61 Cards in this Set
- Front
- Back
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3 clinical settings chemo is used
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1) primary induction treatment for advanced disease 2) neoadjuvant treatment with localized disease 3) adjuvant treatment to local methods of treatment
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curable advanced adult cancers with chemo
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Hodgkins, nonHodkins lymphoma, AML, germ cell cancer, and choriocarcinoma
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curable childhood cancers
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ALL, Burkitt's lymphoma, Wilm's tumor, and embryonal rhabdomyosarcoma
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neoadjuvant treatment
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use of chemo when localized cancer has alternative local therapies, but they are less than completely effective
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what cancers use neoadjuvant treatment
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anal, bladder, breast, esophageal, laryngeal, locally advanced non-small cell lung, and osteogenic sarcoma
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adjuvant chemo goal
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reduce incidence of both local and systemic recurrence and to improve overall survival
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Gompertzian model of tumor growth
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growth fraction of tumor not constant, but decreases exponentially with time
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when does growth fraction peak
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~37% maximum size
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principles that guide selection of drugs in most effective drug combinations
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1) Efficacy 2) Toxicity 3) Optimum scheduling 4) mechanism of interaction 5) avoidance of arbitrary dose changes
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3 main approaches to dose-intensity delivery of chemo
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1) dose escalation 2) reducing interval 3) sequential scheduling
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MDR1 (multi-drug resistance gene)
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encodes cell surface transporter glycoprotein
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alkylating agent MOA
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transfer alkyl groups to various cellular constituents-alkylations of DNA represent major interaction that leads to cell death
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secondary MOA with nitrosoureas (alkylating agent)
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carbamoylation of lysine residues of proteins through formation of isocyanates
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when are cells most susceptible to alkylating agents
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late G1 and S phases; express blockage in G2
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resistance to alkylating agents
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increased capacity to repair DNA lesions, decreased transport of drug into cell, increased production of glutathione and glutathione-associated proteins (needed to conjugate alkylating agent)
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alkylating agents side effects
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carcinogenic (especially AML); GI, bone marrow, and reproductive system; injection site tissue damage; systemic toxictity
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widely used alkylating agent
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cyclophosphamide
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streptozocin (nitrosourea)
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minimal bone marrow toxicity
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Procarbazine MOA
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inhibits DNA, RNA, and protein biosynthsis; prolongs interphase and produces chromosome breaks
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procarbazine is used in
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Hodgkins, nonHodgkins lymphoma
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platimun analogs MOA
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same as alkylating agents; end in -platin
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methotrexate
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folic acid analog that binds with high affinity interfering with synthesis of THF and thus formation of DNA, RNA, and key cellular proteins
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how can biological effects of methotrexate be reversed
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adminstation of reduced folate leucovorin
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vitamen supplementation with folic acid and B12 while on pemetrexed
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appear to reduce toxicities without interfering with clinical efficacy
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cytotoxicity of 5-flurouracil
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combined effects on both DNA and RNA-mediated events; thymineless death
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capecitabine
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fluropyrimidine carbate prodrug
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cytarabine
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S phase specific antimetabolite; incorporated into DNA and RNA; no activity in solid tumors
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gemcitabine tumor effect
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inhibition of ribonucleotide reductase, gemcitabone triphosphate of DNA polymerase-alpha and B; incorporation of gemitabine triphosphate into DNA
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purine antagonists
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6-thiopurines, fludarabine, and cladribine
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fludarabine
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purine nucleotide analog
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cladribine
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purine nucleoside analog; high specificity for lymphoid cells
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vinblastine, vincristine, and vinorelbine (vinka alkyloids)MOA
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inhibition of tubulin polymerization-dirupts assembly of microtubules; derived from periwinkle plant
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Paclitaxel and docetaxel (taxanes) MOA
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mitotic spindle poison through high-affinity binding to microtubules with enhancement of tubulin polymerization
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ixabepilone
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novel microtubule inhibitor-binds B-tubulin subunits on microtubules leading to inhibition of normal microtubule dynamics
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epipodophyllotoxins (eg etopside, teniposide) MOA
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inhibition of topoisomerase II-results in DNA damage through strand breakage induced by formation of ternary complex of drug, DNA, and enzyme
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camptothecins MOA (eg topotecan and irinotecan)
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inhibit activity of topoisomerase I-key enzyme for cutting and religating single DNA stands
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antibiotics in practive as antitumor agents
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products of Streptomyces: antracyclines, bleomycin, and mitomycin
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antracyclines exert cytotoxic action via what 4 mechanisms
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1) inhibition of topoisomerase II 2) high-affinity binding to DNA through intercalation with consequent blockade of RNA and DNA synthesis and DNA strand scission 3) generation of semiquinone free radicals and O2 free radicals through iron-dependent, enzyme mediated 4) binding cellular membranes to alter fluidity and ion transport
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which MOA is cause of cardiotoxicity associated with antracyclines
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free radical mechanism
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antracyclines most important in clinical practice as anticancer agent
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doxorubicin
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AML treatment
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idarubicin plus cytarabine
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dexrazoxane (iron-chelating agent) and antracyclines
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prevent or reduce anthracycline-induced cardiotoxicity in women with metastatic breast cancer
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Mitomycin MOA
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alkylating agent that cross-links DNA
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Bleomycin MOA
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contains DNA and iron binding regions at opposite ends; causes ss and dsDNA breaks following free radical formation; occurs in G2
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imatinib MOA
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inhibitor of tyrosine kinase domain of Bcr-Acl oncoprotein and prevents phosphorylation of kinase substrate by atp
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what other tyrosine kinases does imatinib inhibit
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PDGFR, stem cell factor, and c-kit
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Dasatinib MOA
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inhibitor of several kinases including Bcr-Abl, Src, c-kit, and PDGFR-B; binds active and inactive conformations of Abl kinase domain (unlike imatinib)
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Nilotinib MOA
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inhibits Bcr-Abl, c-kit, and PDGFR-B tyrosine kinases; higher binding affinity for Abl than imatinib
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Cetuximab MOA
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chimeric monoclonal antibody directed against extracellular domain of EGFR
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Panitumumab MOA
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directed against EGFR; G1 isotype as opposed to G1 like Cetuximab-thus doesn't exert immunologic effects
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Gefirinib and Erlotinib MOA
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small molecule inhibitors of tyrosine kinase domain associated with EGFR
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Bevacizumab MOA
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recombinant monoclonal antibody that targets all forms of VEGF-A from interacting with target VEGF receptors
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Sorafenib MOA
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small molecule that inhibits multiple receptor tyrosine kinases, especially VEGF-R2, VEGF-R3, PDGFR-B, and raf kinase
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sunitinib MOA
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similar to sorafenib; inhibits PDGFR-a and B, VEGFR-R1, R2, and R3, and c-kit
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asparaginase MOA
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hydrolyzes circulating L-asparagine to aspartic acid and ammonia; tumor cells in ALL lack asparagine synthetase and require exogenous L-asparagine
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Tretinoin (all-trans-retinoic acid) MOA
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induces terminal differentiation in APL
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arsenic trioxide MOA
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induces differentiation in APL via degradation of chimeric PML/RAR-alpha protein; also induces apoptosis through mitochondrion-dependent process
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major cause of relapse in acute lymphoblastic leukemia
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circulating leukemia cells migrate to brain and testes where they 'hide' from therapy
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Chronic myelogenous leukemia (CML)
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t(9;22) = constitutive expression of Bcr-Abl fusion oncoprotein
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Chronic lymphocytic leukemia (CLL)
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alkylating agents, monoclonal antibodies, purine nuceoside analog all used
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Hodkin lymphoma basics
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B-cell neoplasm in which malignant Reed-Sternberg cells have rearranged VH genes
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