Pharm -3- Chemo Drugs
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| What is a solid tumor arising from epithelial cells | Carcinoma
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| cancer originating from mesenchymal or connective tissue | sarcoma
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| cancers that arise from cells of the hematopoietic system | Leukemias, Lymphomas
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| This is a disease characterized by uncontrolled multiplication and spread of abnormal forms of the body's own cells | cancer (aka malignant neoplasm, malignant tumor)
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| what are the two categories of genetic changes that are important to remember with regard to development of cancers | activation of proto-oncogenes to oncogenes (proto oncogenes normally control cell division, apoptosis, and differentiation) or inactivation of tumor suppressor genes (normally suppress excessive cellular growth)
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| How are malignant tumors different from benign tumors since both show uncontrolled growth | malignant tumor have a capacity for dedifferentiation and loss of function, ability to accumulate mutations, express invasiveness (express metalloprotease that break down extracellular matrix) ability to metastasize (spread from original location
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| What do malignant tumors secrete that allow them to break down extracellular matrix and invade surrounding tissue | metalloprotease
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| Why is it important that malignant tumors are unresponsive to apoptotic signals | this allows them to establish themselves in distant locations
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| What is meant by log kill (kill ratio) | cytotoxic drugs only kill a constant fraction of malignant cells. If it kills 99.99% of cells and you have 10^11 cells you still have .01% of cells left or 10^7 equaling a 4 log kill. You still have a lot of cells to kill. Tx is aimed at a total kill
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| what are the different compartments of cells that tumor cells are classified as | Compartment A- dividing cells continuously in the cell cycle; Compartment B- resting cells in G0 phase not dividing but could begin to; Compartment C- cells not able to divide but contribute to mass of tumor
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| What compartment classification of tumor cells doesn't present a treatment problem | compartment C- they only contribute to mass of tumor and can't start to divide again
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| What compartment classification of tumor cells is actually susceptible to cytotoxic drugs | Compartment A- made of continuously dividing cells that can get target by cytotoxic drugs
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| What compartment of classification of tumor cells presents a problem for tx | Compartment B- cells are in G0 and not actively dividing they are not very susceptible to cytotoxic drugs and could enter compartment A and start actively dividing after tx
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| What is the S phase specific cytotoxic drug group | Antimetabolites
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| What cytotoxic drug group is cell-cycle independent and can target drugs in G0 phase | Alkylating Agents, antitumor antibiotics, nitrosoureas, dacarbazine, cisplatins
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| What cytotoxic drug group targets cells in M phase | taxanes, Vinca alkaloids
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| What cytotoxic drug group targets cells in S-G2 phase | Etoposide
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| What is the MOA of chemotherapeutic agents | primarily prevents cell division- damages DNA inducing cells to undergo apoptosis. Chemotherapy harms cancerous cells and normal cells mostly a balance between which cells are most affected.
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| What are the two groups of chemotherapeutic agents | cell-cycle specific (for hematologic malignancies and solid tumors w/ large growth fraction) and cell-cycle non specific (for solid tumors with low or high growth fraction)
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| What type of chemo agent will you use for hematologic malignancies | cell-cycle specific
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| what broad type of chemo agent will you use for solid tumors with low or high growth fraction | cell-cycle non specific
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| What are the cell cycle specific chemo agents | antimetabolites, Taxanes, Vinca Alkaloids, Antitumor antibiotic Bleomycin, and the epipodophylllotoxins
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| What are the cell cycle nonspecific agents | alkylating agents, Anthracyclines, Antitumor antibiotics (dactinomycin and mitomycin), camptothecin, and platinum analogs
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| What are the acute toxicity s/e of chemo agents | N/V (affects cells of the GI tract), and bone marrow suppression resulting in alopecia, neutropenia, thrombocytopenia. These side effects are often reversible
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| What are the chronic s/e of chemo agents | leukemia, cardiotoxicity (esp. anthracyclines), sterility, neuropathy, nephropathy. These side effects unlike acute are often not reversible
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| What are the alkylating agents | Bis(chloroethyl)amines=Cyclophosphamide, mechlorethamine, Chlorambucil, Melphalan; Nitrosoureas= BCNU (carmustine), CCNU (lomustine), methyl-CCNU (semustine); Alkyl Sulfonate=Busulfan; Aziridines= triethylenemelamine, thiotepa,
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| what is the MOA of the alkylating agents | transfer alkyl group to the DNA at N7 position of guanine resulting in cross linking within a DNA strand or between DNA strands. Causing miscoding, depurination and strand breakage when seen by checkpoint proteins apoptosis is initiated.
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| Are alkylating agents effective against non dividing cells | yes but they are most effective against actively cycling cells
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| What is unique about the MOA of the nitrosoureas as alkylating agents | they alkylate the 06 position of guanine and they have to undergo nonenzymatic conversion to active compound. Most importantly they are lipid soluble and can cross the blood brain barrier
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| If you patient has brain cancer what alkylating agent would you use to help combat their cancer | Nitrosoureas BCNU and CCNU because they are lipid soluble and can cross the BBB
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| what may cause resistance to Alkylating agents and prevent their helping treat cancer in a pt | pt has increased ability to repair DNA, Decreased permeability to agent to area where cancer is located, increased production of glutathione
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| what are the acute and delayed adverse effects of alkylating agents | acute- neurotoxicity causing N/V; Delayed- leukopenia, thrombocytopenia, alopecia, sterility, carcinogenic, Busulfan can cause pulmonary fibrosis and hepatic toxicity
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| what is a major concern of using the alkylating agent Busulfan for treating cancers | it has an adverse effect of causing pulmonary fibrosis and hepatic toxicity
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| what alkylating agent can be taken orally to combat NHL, ovarian and breast cancers and neuro blastoma | Bis(chlorethyl)amines- such as cyclophosphamide, mechlorethamine, chlorambucil, melphalan
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| What is a concern with using cyclophosphamide to treat cancer | it must be activated in liver it has a cytotoxic metabolite Acrolein that can cause hemorrhagic cystitis and mesna reacts with it to create an inactive compound. It also causes hepatic toxicity
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| What is the only alkylating agent that Bis(chorethyl)amines don't have a cross-resistance with | nitrosoureas
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| what chemo agent form complexes with DNA causing intra and inter strand cross links resulting in cytotoxic effects but has nephrotoxicity, ototoxicity. Used for testicular, ovarian, bladder and lung cancers | Cisplatin and other platinum analogs
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| What is the second generation platinum analog that has replaced cisplatin and why | carboplatin- has less nephrotoxicity and GI toxicity. Myelosuppression is main dose limiting toxicity don't combine with drugs that have same dose limiting toxicity
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| What is the third generation platinum analog | oxaliplatin
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| What is the MOA of the antimetabolites | antimetabolites affect nucleotide and nucleic acid synthesis creating bottlenecks in the major enzyme pathways to creating these building blocks of DNA as a group antimetabolites don't cause acute toxicities
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| What is the MOA of methotrexate | as a folic acid antagonist if binds the active site of DHFR and prevents the production of reduced folate. This interferes with the formation of DNA and RNA and key cellular proteins. Stops formation of thymidine by dUMP
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| Does methotrexate cross the BBB | no but can be administered intrathecally to act on cells in sanctuary sites in the brain
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| What properties may cause a drug resistance to methotrexate | decreased drug transport into the cell, increased synthesis of DHFR, DHFR with decreased affinity for MTX, decreased cellular retention of MTX
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| What are the adverse effects of methotrexate | mucositis-diarrhea, Bone Marrow depression (leukopenia, thrombocytopenia). These effects can be prevented by rescue with leucovorin. Also has nephrotoxicity (keep patient well hydrated and generally not a problem)
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| What is the therapeutic use of methotrexate | leukemias, lymphomas and breast cancer
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| what antimetabolite is used to tx acute lymphocytic leukemia | 6-thiopurines- 6-mercaptopurine and 6-thioguanine
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| What is the moa of the 6-thiopurines | they get converted to by HGPRT to active form and then inhibit enzymes required for purine synthesis blocking formation of DNA and RNA and leads to DNA and RNA using thiopurine
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| What are the toxicity problems with the 6-thiopurines | cause myelosuppression, immunosuppression and hepatotoxicity
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| What causes a drug resistance to 6-thiopurines | Resistance is common through decreased expression of HGPRT the enzyme needed to convert the 6-thiopurines into their active metabolite
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| What is the MOA of the antimetabolite 5-fluorouracil | prodrug that undergoes a series of biotransformations to become fdUMP, this can prevent synthesis of thymidine. It can also be converted to FUTP which can get incorporated into RNA or can be incorporated into DNA as fdUTP
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| How do you have to give 5-fluorouracil | IV because it will be broken down in the gut
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| what are the adverse effects of 5-fluorouracil | Nausea, Diarrhea, mucositis, bone marrow depression, alopecia, hand foot syndromes
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| What is the therapeutic uses for 5-fluorouracil | breast, ovarian head and neck cancers
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| why is leucovorin given with 5-fluorouracil (the fol-fox regimen) | It helps potentiate the actions of 5-FU b stabilizing the ternary complex it forms with thymidylate preventing synthesis of thymidine
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| What is the MOA of gemcitabine an antimetabolite | it get phosphorylated to become active then inhibits ribonucleotide reductase decreasing pool of nucleotides for DNA synthesis. DNA chain termination follows after it gets incorporated into the DNA.
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| What is the toxicity of Gemcitabine | myelosuppression is the principle does limiting toxicity, also causes N/V and diarrhea
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| What cytotoxic agents shouldn't be combined because they both cause myelosuppression and that is their dose limiting toxicity | Gemcitabine, Carboplatin, anthracyclines
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| What is the therapeutic use for Gemcitabine | non small cell lung cancer, bladder cancer, non Hodgkins lymphoma
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| What is the MOA of the Vinca alkaloids vinblastine, vincristine, and vinorelbine | inhibit tubulin polymerization by binding b-tubulin and prevents its interaction with a-tubulin preventing assembly of microtubules. Cell division gets stuck at metaphase because cell chromosomes can't separate leads to cell apoptosis
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| What can cause a drug resistance to Vinca alkaloids | increased drug efflux, cross resistance with any drug that is substrate for transporters MDR, p-glycoprotein
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| What is the adverse effect of the Vinca alkaloids | alopecia, local cellulitis, hyperuricemia (give allopurinol), hepatic elimination
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| What is the s/e of vinblastine a Vinca alkaloid | painful ulceration if extravasation occurs, myelosuppression, least likely of them to cause neurotoxicity but causes GI problems
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| What are the s/e of vincristine Vinca alkaloid | limited myelosuppression great to combine with those that are myelosuppressive. Neurotoxic effects (numbness tingling motor weakness, constipation) less GI effects, may cause SIADH
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| What are the s/e of vinorelbine a Vinca alkaloid | myelosuppressive, granulocytopenia, low neurotoxicity may cause SIADH
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| What are the therapeutic uses of vinblastine | Hodgkin, NHL, breast cancer, testicular
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| What are the therapeutic uses for vincristine | ALL, Hodgkin, Leukemias, Wilms (cancer of the kidney)
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| What are the therapeutic uses for vinorelbine | non-small cell lung cancer, breast cancer
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| What is the MOA of Taxanes (paclitaxel, docetaxel) | binds to Beta-Actin to promote formation of microtubules causing atypical microtubule structures during M phase arrests mitosis leading to apoptosis
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| What can cause resistance to Taxanes | P-glycoprotein, B-tubulin mutations
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| What are the adverse effects of taxanes | myelosuppressive, cumulative neurotoxicity, mucositis, alopecia, hypersensitivity reaction (pretreat with corticosteroids and antihistamines) docetaxel causes fluid retention and edema
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| What are the therapeutic uses for paclitaxel | broad range of solid tumors ovarian, breast, lung, head, neck
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| What are the therapeutic uses for docetaxel | non-small cell lung cancer, head, neck, ovarian and bladder cancers
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| What is the MOA of the epipodophyllotoxins | inhibit DNA topoisomerase II by forming ternary complex with topoisomerase, the DNA and the drug leading to strand breakage blocks cell division in late s-G2 phase
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| What are the adverse effects of epipodophyllotoxins | dose reduction in renal dysfunction
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| What are the therapeutic uses for etoposide | lung caner, Hodgkin, NHL
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| What are the therapeutic uses for teniposide | ALL
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| What is the MOA of the anthracyclines (Doxorubicin, daunorubicin, idarubicin, epirubicin, Mitoxantrone) | minor: inserts between base pair of DNA and RNA disrupting function; Major action is to inhibit topoisomerase II causing breaking of DNA strand
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| What are the adverse effects of using anthracyclines | myelosuppression acute dose limiting toxicity, conversion to free radical can cause tissue damage causing cardiotoxicity, dose related N/V, damage due to extravasation,
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| What is the therapeutic use for the anthracycline doxorubicin | Acute leukemias, lymphomas, solid tumors
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| What is the use for the anthracycline daunorubicin | acute myeloid leukemia
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| what is the MOA of bleomycin | one end binds DNA and the opposite end chelates Fe2+ oxidation of complex causes DNA fragmentation and stops cell cycle at G2
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| What are the adverse effects of bleomycin | pulmonary fibrosis is the dose limiting toxicity, mucocutaneous reaction often involving palms of feet and hands. Low myelosuppression and alopecia
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| What are the therapeutic uses for bleomycin | Hodgkin, testicular, head, neck, skin cancers
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| what is the MOA for dactinomycin (actinomycin D) | intercalation, inhibition of topoisomerase II
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| What are the adverse effects of Dactinomycin (actinomycin D) | N/V bone marrow depression
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| What are the therapeutic uses for dactinomycin | pediatric tumors
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| what is the MOA for the hormonal agent Prednisone | acts through glucocorticoid receptor to cause lymphocytopenia and decreases lymphoid mass it is metabolized in the liver to active form
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| What are the therapeutic uses for prednisone | induces remission in ALL, treatment of Hodgkin's and NHL
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| What is the MOA for Tamoxifen | competitive partial agonist inhibitor of estrogen. Lower affinity than estradiol at estrogen receptor must ablate endogenous estrogen
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| What are the s/e of tamoxifen | menopausal symptoms
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| What are the therapeutic uses of tamoxifen | breast cancer
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| what is the MOA of flutamide and bicalutamide | antagonist at the androgen receptor
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| what are the s/e of flutamide and bicalutamide | hot flashes and mild nausea
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| what is the therapeutic use for flutamide and bicalutamide | prostate cancer
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| what is the MOA of gonadotropin releasing hormone agonists | inhibits the release of testosterone to near castration levels
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| What are the adverse effects of gonadotropin releasing hormone agonists | hot flashes, impotence, gynecomastia
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| What is the therapeutic use for gonadotropin releasing hormone agonists | prostate cancer
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| what is the MOA of aromatase inhibitors (anastrozole, letrozole, exemestane) | inhibit conversion of estrogen from androgen by aromatase
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| what are the adverse effects of aromatase inhibitors | mild nausea, headache, fatigue, hot flushes, arthralgias
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| what are the therapeutic uses for aromatase inhibitors | breast cancer
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| What is the MOA of monoclonal antibodies | cytotoxicity based on antibody dependent lysis, complement dependent lysis, localize delivery of radiation, localize delivery of chemotherapy, inhibit angiogenesis
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| What is the class toxicity of using monoclonal antibodies | cytokine release reaction that may be sever with fever chills and hypotension
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| What is he MOA of tyrosine kinase inhibitor imatinib | inhibits platelet derived growth factor and intracellular kinase pathways
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| what adverse effects does tyrosine kinase inhibitor imatinib have | N/D, GI pain, fatigue and headache
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| What is the therapeutic use for imatinib a tyrosine kinase inhibitor | chronic myeloid leukemia
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| why is combining chemo agents helpful and what must you avoid | by combining agents you can decrease likelihood of developing resistance and drugs can be used at full doses just don't combine drugs with same limiting toxicity
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| what are the bone marrow sparring agents | cisplatin, bleomycin, vincristine
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| study slide 39 | study slide 39
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