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151 Cards in this Set
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Anticancer agents that act on tumor stem cells when they are traversing the cell cycle and when they are in the resting phase
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CCNS drugs
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An anticancer agent that acts selectively on tumor stem cells when they are traversing the cell cycle and not when they are in the G0 phase
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CCS drug
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The proportion of cells in a tumor population that are actively dividing
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Growth fraction
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A mutant form of a normal gene that is found in naturally occurring tumors and which, when expressed in noncancerous cells, causes them to behave like cancer cells
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oncogene
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A drug that causes blisters on contact w/ tissues. Such drugs can be particularly damaging to veins if administered in high concentrations into small vessels
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Vesicant
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Mechanism of resistance particularly important for alkylating agent and cisplatin
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Increased DNA repair
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Some tumor cells increase their production of thiol trapping agents (eg. glutathione), which interact w/ anticancer drugs that form reactive electrophilic species
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Formation of trapping agents
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Mechanism of resistance seen w/ the alkylating agent bleomycin, cisplatin, and the anthracyclines
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Formation of trapping agents
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Mechanism of resistance to methotrexate
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Changes in the drug sensitivity of a target enzyme, dihydrofolate reductase, and increased synthesis of the enzyme
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Mechanism of resistance to the purine antimetabolites (mercaptopurine, thioguanine) and the pyrimidine antimetabolites (cytarabine, fluorouracil)
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Decrease in the activity of the tumor cell enzymes needed to convert these prodrugs to their cytotoxic metabolites; inactivation due to increased activity of inactivating enzymes
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This form of multidrug resistance involves the increased expression of a normal gene (the MDR1 gene) for a cell surface glycoprotein (P-glycoprotein)
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Decreased drug accumulation due to accelerated efflux
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Part of the cell cycle that alkylating agents act on
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CCNS
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Form reactive molecular species that alkylate nucleophilic groups on DNA bases, particularly the N-7 position of guanine. This leads to cross-linking of bases, abnormal base pairing, and DNA strand breakage
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Alkylating agents
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Resistance to Alkylating agents occurs through these mechanisms
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Increased DNA repair, decreased drug permeability and the production of trapping agents such as thiols
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MOA of cyclophosphamide
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Hepatic cytochrome P450-mediated biotransformation of cyclophosphamide is needed for anti-tumor activity
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Major breakdown product of cyclophosphamide
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acrolein
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Clinical use of cyclophosphamide
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non-Hodgkin's lymphoma, breast and ovarian cancers and neuroblastoma
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Toxicity of cyclophosphamide
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GI distress, myelosuppression, and alopecia; hemorrhagic cystitis resulting from the formation of acrolein can occur; cardiac dysfunction, pulmonary toxicity, and SIADH
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Way to decrease hemorrhagic cystitis resulting from the formation of acrolein while using cyclophosphamide
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Vigorous hydration and by use of MESNA
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Clinical use of mechlorethamine
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Hodgkin's lymphoma
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Toxicity of mechlorethamine
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GI distress, myelosuppression, alopecia, and sterility; marked vesicant actions
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Cisplatin, Carboplatin, oxaliplatin
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Platinum analogs
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Clinical use of Cisplatin
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Component of regimens for testicular carcinoma and for cancers of the bladder, lung, and ovary
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Clinical use of oxaliplatin
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Advance colon cancer
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Toxicity of Cisplatin
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GI distress and mild hematotoxicity and is neurotoxic(peripheral neuritis and acoustic nerve damage) and nephrotoxicity
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Way to reduce renal damage caused by Cisplatin
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Use of mannitol w/ forced hydration
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Dose limiting toxicity of oxaliplatin
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neurotoxicity
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MOA of Procarbazine
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Reactive agent that forms hydrogen peroxide, which generates free radicals that cause DNA stand scission (alkylating agent)
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Primary use of Procarbazine
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Component of regimens for Hodgkin's lymphoma
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Toxicity of Procarbazine
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Myelosuppression and GI irritation, CNS dysfunction, peripheral neuropathy, and skin rxns; inhibit many enzymes, including MAO and those involved in hepatic drug metabolism; Disulfiram like rxns w/ ethanol; leukemogenic
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Clinical use and toxicity of Busulfan (alkylating agent)
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CML; adrenal insufficiency, pulmonary fibrosis, and skin pigmentation
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Alkylating agents that are highly lipid soluble drugs used as adjuncts in the management of brain tumors
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Carmustine (BCNU) and lomustine (CCNU)
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Clinical use and toxicity of Dacarbazine (alkylating agent)
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Hodgkin's lymphoma; alopecia, skin rash, GI distress, myelosuppression, phototoxicity, and a flulike syndrome
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Stage of the cell cycle that antimetabolites act
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S phase
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MOA of methotrexate
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A substrate and inhibitor of dihydrofolate reductase. The formation of polyglutamate derivatives of methotrexate is important for cytotoxic actions
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Mechanism of resistance to methotrexate
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Decreased drug accumulation, changes in the drug sensitivity or activity of dihydrofolate reductase, and decreased formation of polyglutamates
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Clinical use of methotrexate
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Choriocarcinoma, acute leukemias, non-Hodgkin's and cutaneous T cell lymphomas, and breast cancer; also used in RA psoriasis and ectopic pregnancy and as an abortifacient
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Toxicity of methotrexate
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Bone marrow suppression and toxic effects on the skin and GI mucosa (mucositis); long term use can cause hepatoxicity and pulmonary infiltrates and fibrosis
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Toxic effects of methotrexate on normal cells may be reduced by administration of:
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Folinic acid (leucovorin)- "Leucovorin rescue"
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MOA of Mercaptopurine (6-MP) aand Thioguanine (6-TG)
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Purine antimetabolites that are activated by hypoxanthine-guanine phosphoribosyltransferases (HGPRTases) to toxic nucleotides that inhibit several enzymes involved in purine metabolism
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Mechanism of resistance to purine metabolites (6-MP and 6-TG)
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Decreased activity of HGPRTase or they may increase their production of alkaline phosphatases that inactivae the toxic nucleotides
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Drug that inhibits the metabolism of 6-MP by xanthine oxidase
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allopurinol
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Clinical use of purine antimetabolites (6-MP and 6-TG)
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mainly in acute leukemias and CML
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Toxicity of purine antimetabolites (6-MP and 6-TG)
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Bone marrow suppression is dose limiting and hepatic dysfunction also occurs
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MOA of Fluorouracil (5-FU)
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5-FU is converted in cells to 5-FdUMP which inhibits thymidylate synthase and leads to "thymineless death" of cells (pyrimidine antimetabolites)
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Mechanism of resistance to 5-FU
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Decreased activation of 5-FU, increased thymidylate synthase activity, and reduced drug sensitivity of this enzyme
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Clinical use of 5-FU
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bladder, breast, colon, head and neck, liver, and ovarian cancers; topically for karatoses and superficial basal cell carcinoma
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Toxicity of 5-FU
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GI distress, myelosuppression, and alopecia
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MOA of cytarabine (ARA-C)
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A pyrimidine antimetabolite, activated by kinases to AraCTP, an inhibitor of DNA polymerases
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Of all the antimetabolites, this drugis the most specific for the S phase of the cell cycle
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Cytarabine
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mechanism of resistance to cytarabine (ARA-C)
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Decreased uptake or its decreased conversion to AraCTP
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MOA of Gemcitabine
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Deoxcytidine analog (pyrimidine antimetabolite) that is converted into the active diphosphate & triphosphate nucleotide form. Gemcitabine diphosphate appears to inhibit ribonucleotide reductase and thereby diminish the pool of deoxyribonucleoside triphosphates required for DNA synthesis. Gemcitabine triphosphate can be incorporated into DNA, where it causes chain termination
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Clinical use of Gemcitabine
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pancreatic cancer, non-small cell lung cancer, bladder cancer and non-Hodkin's lymphoma
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Toxicity of Gemcitabine
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Primarily myelosuppresion, mainly as neutropenia; pulmonary toxicity
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MOA of Vinca alkaloids (Vinblastine, Vincristine, Vinorelbine)
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Block the formation of the mitotic spindle by preventing the assembly of tubulin dimers into microtubules
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Phase of the cell cycle that the vinca alkaloids primarily act on
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M-phase
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mechanism of resistance of the vinca alkaloids
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Increased efflux of the drugs from tumor cells via the membrane drug transporter
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Clinical use of Vincristine
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Acute leukemias, lymphomas, Wilm's tumor, and choriocarcinoma
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Clinical Use of Vinblastine
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Lymphomas, neuroblastoma, testicular carcinoma, and Kaposi's Sarcoma
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Clinical use of Vinorelbine
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Non-small cell lung cancer and in breast cancer
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Toxicity of Vinblastine and vinorelbine
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GI distress, alopecia, and bone marrow suppression
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Toxicity of Vincristine
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Neurotoxic actions and may cause areflexia, peripheral neuritis, and paralytic ileus
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MOA of Etoposide
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Increases degradation of DNA, possibly via interaction w/ topoisomerase II, and also inhibits mitochondrial electron transport (plant alkaloid-podophyllotoxins)
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Phase of the cell cycle that Etoposide is most active in
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Late S and early G2 phases
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Clinical use of podophyllotoxins (etoposide, teniposide)
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Small cell lung cancer, prostate, testicular carcinoma
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Toxicity of podophyllotoxins ( etoposide, teniposide)
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GI irritants, alopecia, bone marrow suppression
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MOA of Camptothecins (topotecan, irinotecan)
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Inhibit topoisomerase I: they damage DNA by inhibiting an enzyme that cuts and relegates single DNA strands during normal DNA repair processes
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Clinical use of Topotecan
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2nd line therapy for advance ovarian cancer and for small cell lung cancer
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Clinical use of Irinotecan
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Metastatic colorectal cancer
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Most common toxicities of Camptothecins (topotecan, irinotecan)
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Myelosuppression and diarrhea are the 2 most common toxicities
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MOA of taxones (Paclitaxel & Docetaxel)
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Interfere w/ the mitotic spindle by preventing microtubule disassembly into tubulin monomers
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Clinical use of taxones (Paclitaxel and Docetaxel)
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Advanced breast and ovarian cancers
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Toxicity of Paclitaxel
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Neutropenia, thrombocytopenia, a high incidence of peripheral neuropathy, and possible hypersensitivity rxns during infusion
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Toxicity of Docetaxel
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Neurotoxicity and bone marrow depression
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MOA of anthracyclines (Doxorubicin and Daunorubicin)
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Intercalate b/w base pairs, inhibit topoisomerase II, and generate free radicals. They block the synthesis of RNA and DNA and cause DNA strand scission
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Phase of the cell cycle that anthracyclines (Doxorubicin and Daunorubicin) act
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CCNS
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Clinical use of Doxorubicin
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Hodgkin's lymphoma, myelomas, sarcomas, and breast, endometrial, lung, ovarian, and thyroid cancers
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Main use of daunorubicin
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Acute Leukemias
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Clinical use of Idarubicin, a new anthracycline
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AML
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Toxicity of anthracyclines (Doxorubicin and Daunorubicin)
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Bone marrow suppression, GI distress, severe alopecia; most distinctive AR is cardiotoxicity, which includes ECG abnormalities and slowly developing cardiomyopathy and CHF
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Used in the treatment of T cell autotrophic cancers (leukemia and lymphomas) that may require exogenous asparagine for growth
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Asparaginase
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Toxicity of Asparaginase
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Severe hypersensitivity rxns, acute pancreatitis, and bleeding
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Inhibits the tyrosine kinase activity of the protein product of the Bcr-Abl oncogene that is commonly expressed in CML; & is also effective for treatment of GI stromal tumors that express the c-kit tyrosine kinase, which is also inhibited
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Imatinib
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Toxicity of Imatinib
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Diarrhea, myalgia, and fluid retention
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Endogenous glycoproteins w/ antineoplastic, immunosuppressive, and antiviral actions
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Interferons
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Clincal use of alpha-interferons
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Hairy cell leukemia, the early stage of CML, and T-cell lymphomas
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Toxicity of interferons
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Myelosuppression and neurologic dysfunction
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A monoclonal antibody that binds to a surface protein in non-Hodgkin's lymphoma cells & induces complement mediated lysis, direct cytotoxicity and induction of apoptosis
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Rituximab
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A monoclonal antibody, recognizes a surface protein in breast cancer cells that over express the HER-2/neu receptor for epidermal growth factor
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Trastuzumab
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Toxicity of Trastuzumab
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nausea and vomiting, chills, fevers and headache; cardiac dysfunction including CHF
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A monoclonal antibody directed to the extracellular domain of the EGFR; used in combo w/ irinotecan and oxaliplatin for metastatic colon cancer and is used in combo w/ radiation ofr head and neck cancer
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Cetuximab
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Primary toxicity of Cetuximab
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Skin rash and hypersensitivity rxn
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Monoclonal antibody that binds to VEGF and prevents it from interacting w/ VEGF receptors; VEGF plays a critical role in the angiogenesis required for tumor metastasis
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Bevacizumab
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Clinical use of Bevacizumab
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metastatic colorectal cancer
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AE of Bevacizumab
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HTN, arterial thrombosis, impaired wound healing, GI perforation, and proteinuria
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This inhibitor of iron mediated free radical generation, may protect against anthracycline cardiotoxicity
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Dexrazoxane
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MOA of Bleomycin
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A mixture of glycopeptides that generates free radicals, which bind to DNA, cause strand breaks, and inhibit DNA synthesis
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Phase of cell cycle that Bleomycin is active
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G2
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Clinical use of Bleomycin
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Component of drug regimens for Hodkin's lymphoma and testicular cancer; tx of lymphomas and for squamous cell carcinomas
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Toxicity of bleomycin
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Pulmonary dysfunction (pneumonitis, fibrosis), which develops slowly and is dose limiting; hypersensitivity rxns are common, as are mucutaneous rxns (alopecia, blisters, hyperkeratosis)
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A CCNS drug that binds to double-stranded DNA and inhibits DNA-dependent RNA synthesis
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Dactinomycin
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Clinical use of Dactinomycin
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Melanoma and Wilm's tumor
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Toxicity of Dactinomycin
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Bone marrow suppression, skin rxns, and GI irritation
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A CCNS drug that is metabolized by liver enzymes to form an alkylating agent that cross-links DNA
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Mitomycin
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Clinical use mitomycin
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Acts against hypoxic tumor cells and is used in combination regimens for adenocarcinomas of the cervix, stomach, pancreas, and lung
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Toxicity of mitomycin
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severe myelosuppression and isotoxic to the heart, liver, lung and kidney
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Most commonly used glucocorticoid in cancer chemo and is widely used in combination therapy for leukemias and lymphomas
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Prednisone
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A selective estrogen receptor modulator that blocks the binding of estrogen to receptors of estrogen-sensitive cancer cells in breast tissue
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Tamoxifen
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Toxicity of Tamoxifen
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B/C it has agonist activity in the endometrium, it increases the risk of endometrial hyperplasia and neoplasia; nausea, vomiting, hot flushes, vaginal bleeding, and venous thrombosis
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Androgen receptor antagonist used in prostatic carcinoma
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Flutamide
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AEs of Flutamide
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gynecomastia, hot flushes, and hepatic dysfunction
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GnRH agonists effective in prostatic carcinoma
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Leuprolide, goserelin, and nafurelin
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MOA of GnRH analogs
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Inhibit release of pituitary LH and FSH
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Inhibit aromatase, the enzyme that catalyzes the conversion of androstendione (an androgenic precursor) to estrone
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Aromatase inhibitors(Anastrozole and letrozole)
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Clinical use of Aromatase inhibitors (Anastrozole and letrozole)
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Advanced breast cancer
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Toxicity of Aromatase inhibitors (Anastrozole and letrozole)
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Nause, diarrhea, hot flushes, bone and back pain, dyspnea, and peripheral edema
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Constant proportion of cell population killed rather than a constant number
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Log-kill hypothesis
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Tx w/ cancer chemo at high doses every 3-4 weeks b/c of toxicity in continual dosing
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Pulse therapy
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Drug used concurrently w/ toxic anticancer agents to reduce renal precipitation of urates
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Allopurinol
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Pyrimidine analog that causes "Thymine-less death" given w/ leucovorin rescure
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5-Flouracil (5-FU)
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Drug used in cancer therapy that causes Cushing-like symptoms
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Prednisone
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SE of mitomycin
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SEVERE myelosuppression
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MOA of cisplatin
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Alkylating agent
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Common toxicities of cisplatin
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Nephro and ototoxicity
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Analog of hypoxanthine, needs HGPRTase for activation
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6-mercaptopurine (6-MP)
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Interaction w/ this drug requires dose reduction of 6-MP
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Allopurinol
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May protect against doxorubicin toxicity by scavenging free radicals
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Dexrazoxane
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Blows DNA (breaks DNA strands), limiting SE is pulmonary fibrosis
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Bleomycin
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Bleomycin + vinblastine+etoposide+cisplatin produce almost 100% response when all agents are used for this neoplasm
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Testicular cancer
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MOPP regimen used in Hodkin's disease (HD)
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Mechlorethamine+ Oncovorin (vincristine) + procarbazine, and prednisone
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ABVD regimen used for HD, but appears less likely to cause sterility and secondary malignancies than MOPP
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Adriamycin (doxorubicin) +bleomycin, vinblastine+dacarbazine
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Regimen used for non-Hodgkin's lymphoma
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COP (cyclophosphamide, oncovin (vincristine), and prednisone)
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Regimen used for breast cancer
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CMF (cyclophosphamide, methotrexate, and fluorouracil, and tamoxifen if ER)
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Alkylating agent, vesicant that causes tissue damage w/ extravasation
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Mechlorethamine
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Anticancer drug also used in RA, produces acrolein in urine that leads to hemorrhagic cystitis
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Cyclophosphamide
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Prevention of cyclophosphamide induced hemorrhagic cystitis
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Hydration and MESNA
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Microtubule inhibitor that causes peripheral neuropathy, foot drop (eg ataxia), and "pins and needles' sensation
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Vincristine
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Interact w/ microtubules (but unlike vinca which prevent disassembly of tubules), it stabilizes tubulin and cells remain frozen in metaphase
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Paclitaxel (taxol)
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Toxicities include nephrotoxicity and ototoxcity, leading to a severe interaction w/ aminoglycosides
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Cisplatin
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Agent similiar to cisplatin, less nephrotoxic, but greater myelosuppression
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Carboplatin
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Converts asparagine to aspartate and ammonia, denies cancer cells of the essential AA asparagine
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L-asparagine
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Used for hair cell leukemia, it stimulates NK cells
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Interferon Alpha
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Anti-androgen used for prostate cancer
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Flutamide
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Anti-estrogen used for estrogen receptor + breast cancer
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Tamoxifen
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Aromatase inhibitor used in breast cancer
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Letrozole, anastrozole
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Newer estrogen receptor antagonist used in advanced breast cancer
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Toremifene (fareston)
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Cell cycle specific anti-cancer drugs
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Bleomycin, vinca alkaloids, antimetabolites (eg 5-FU, 6-MP, methotrexate, etoposide)
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Cell cycle non-specific anti-cancer drugs
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Alkylating agents, antibiotics, cisplatin, nitrosourea
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Anti-emetics used in assoc w/ anti-cancer drugs that are 5-HTS (serotonin receptor subtype) antagonist
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Odansetron, granisetron
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Nitrosoureas w/ high liphophilicity, used for brain tumors
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Carmustine (BCNU) and lomustine (CCNU)
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Produces disulfiram-like rxn w/ ethanol
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Procarbazine
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