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112 Cards in this Set
- Front
- Back
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what are the three types of cancer drug therapies
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classical drugs which nonspecifically target growing cells, hormones/anti-hormones, targeted approaches
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what is one major drawback to classical drugs
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they don't target specific cells so they have bone marrow suppression (RBC, WBC, and platelet suppression). this bone marrow suppression is dose limiting so if you give too much you kill the patient
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how do monoclonal cancer cells become heterogenous in their genetics
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b/c of changes in environmental factors like nutrients and growth factors. these changes are influenced by position within the tumor and location of metastases. also cancer cells have unstable genomes. this genetic heterogenity makes therapy difficult
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what are some ways cancer cells may be different from normal cells that may be used for chemotherapy
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1. growth kinetics
2. hormone dependence 3. immune response (ie different markers on them) 4. selective inhibition |
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what types of cells does chemotherapy suppress
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normal proliferating cells like cells in bone marrow, GI tract, germinal epithelia (sterility problem), hair follicles, and lymphoid organs
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if you're gonna use a combination of chemotherapy drugs what kinds of drugs do you try to choose
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chemotherapy drugs with different toxicities and different mechanisms of action
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when do you find most tumors clinically and what happens as the tumor grows
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1 cm is 1 x 10 9 cells. as tumor grows the doubling time increases
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what is growth fraction and how does it relate to chemotherapy effectiveness
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percentage of cells dividing. tumors with high growth fractions are weak against chemo. that's why you decrease the size of tumors with surgery, etc
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what is the log kill hypothesis
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Number killed = Number of tumor cells x K, where K is constant determined by dose of drug and drug type. number killed is proportional to the number of cells
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what do you decrease prior to chemotherapy
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tumor burden is often reduced prior to chemotherapy either thru surgery or radiation
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how do you administer chemotherapy
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as a consequence of the log kill theory, among other things, drugs are given at maximum dose as often as possible. the minimal interval between doses is determined by the ability of normal tissues to recover
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why do we use chemo drugs in combination
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resistance develops rapidly to single drugs, heterogeneity of cells, each drug with a different mechanism has maximum log kill.
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what is an example of natural chemo drug resistance
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multi-drug resistance MDR1 annd MDR2 drug pumps may be upregulated by mutations in cancer cells. their normal function in places like the GI tract is to pump stuff out of GI tract cells.
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how do you figure out drugs for chemotherapy
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first do in vitro assays using chemicals and hormones to see which types of tumors are weak against the drug. then you look at tumor sensitivity to drugs during clinical trials.
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what is adjuvant therapy
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treatment to block reoccurence of cancer following primary treatment (e.g. tumor removal via surgery or radiation treatment)
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what are the mechanisms of action of the classic chemotherapeutic drugs
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DNA damaging agents (crosslinking and alkylating agents, DNA cleaving agents), metabolic analogs (enzyme inhibitors and nucleotide analogs), inhibitors of mitosis
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what type of classic chemotherapeutic drugs can cause more cancers later on
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DNA damaging agents which can cause more mutations later on. DNA breakage agents, a type of DNA damaging agents, doesn't cause more cancers later on because they kill cells
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what class of drug is cyclophosphamide. mechanism of action
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classical drug, nitrogen mustard, DNA damaging agent that cross-links DNA by covalently binding to DNA bases
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what is the general mechanism of nitrogen mustards
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they cross link by losing a chloride, covalently binding to the N7 guanine, then binding another base by the same mechanism
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how do cancer cells develop a resistance to nitrogen mustards
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upregulating of enzymes that uncrosslink DNA
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how do nitrogen mustards kill cells
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cross link DNA so no longer make RNA because template function of DNA is lost. a cell without protein = dead cell
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cyclophosphamide works on which phases
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nonphase specific
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cyclophosphamide major side effect
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bone marrow suppression and bladder dysfunction (handled by MENSA)
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cyclophosphamide, before it works it needs to be
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activated by P450 enzymes which give you phosphoramide mustard and nornitrogen mustard which are both active crosslinkers. it also gives you acrolein which causes bladder dysfunction
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how do you treat bladder dysfunction caused by cyclophosphamide
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via MESNA which prevents hemorrhagic cystitis (diffuse inflammation of the bladder leading to dysuria, hematuria, and hemorrhage) by inactivating acolein so that it can be safely excreted in the urine without causing bladder damage. dimer in the plasma. kidney makes it into a monomer that can do its thing
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what kind of drugs is cisplatin
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platinum analog that's a DNA cross-linker
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what phase does cisplatin work on
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phase non-specific
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what major toxicity does cisplatin have
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renal toxicity
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what drugs can you use MESNA for
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cyclophosphamide and ifosfamide. both to prevent acrolein induced bladder damage
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how do you limit renal toxicity of cisplatin
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load the patient up on saline which mitigates the release of chlorides
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cisplatin mechanism of action
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DNA cross-linker which releases chlorides and then is able to cross-link DNA bases
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what are the DNA cleaving drugs
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Bleomycin and Doxorubicin
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what are the DNA cross linking drugs
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cyclophosphamide and cisplatin
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what phases does bleomycin work on
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more active in M or G2
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what phases does doxorubicin work on
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phase nonspecific
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what is bleomycin's mechanism of action
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after its activated by microsomal reduction, structure lets it bind to DNA. it also binds to iron and this generates superoxide ions (ROS) than can cleave DNA
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what is bleomycin's major toxicity
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pulmonary toxicity is the dose limiting toxicity
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what is doxorubicin's mechanism of action
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intercalates between DNA, freezes topoisomerase II (enzyme that unwinds and winds DNA during synthesis of mRNA) causing DNA cleavage
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what is doxorubicin's dose limiting toxicity
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CARDIAC TOXICITY (cumulative heart damage leading to congestive heart failure) and bone marrow suppression
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what population is doxorubicin good for
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very effective in breast cancer patients that aren't hormonely response
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how do antimetabolites work
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they are structural analogs of naturally occurring compounds. they work via competitive inhibition (e.g. folic acid analog) or premature chain termination (e.g. RNA and DNA - base analogs)
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what is methotrexates mechanism of action
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folic acid analog that competitively inhibits dihydrofolate reducatse (DHFR) which makes dihydrofolate (FH2) to tetrahydrofolate (FH4). this causes a shortage of pyrimidines, purines, protein synthesis. this eventually leads to cell death
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what are some ways a cell can develop a resistance to methotrexate
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inhibit its transport into cells, inhibit the polyglutamate formation that keeps it inside cells, increase or alter dihydrofolate reducatse
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what is methotrexates major toxicity
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bone marrow suppression
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what phase is methotrexate specific for
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S-phase specific
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what is methotrexate used for
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low dose: maintenance of remission phase of lymphoblastic leukemia (excessive lymphoblasts) (non-effective concentration in CNS)
high dose: osteosarcoma and non-hodgkin's lymphoma (any form of lymphoma that isn't hodgkin's lymphoma: orderly spread of disease from one lymph node group to another and the development of systemic symptoms with advanced disease) (use with leucovorin) (effective concentration in the CNS) |
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what dosages is methotrexate used at
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standard doses: 30 mg/m2 2x a week or 175 mg/m2 twice a month. it can be given intrathecally to increase CNA concentration. high doses: 250 mg/m2 for 6 hours followed by doses of leucovorin 15 mg/m2 every six hours for a total of seven doses
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what is done to mitigate methotrexate's untoward effects
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at the high doses used for treating osteosarcoma and non-hodgkin's lymphomas, you have lots of toxic effects. that's why you give leucovorin (reduced folate) which is enough to save normal cells. tumor cells aren't saved enough by leucovorin.
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what is fluorouracil's mechanism of action
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a pyrimidine analog. prevents formation of mature 28s ribosomes. it can cause DNA strand breaks by incorporation. inhibits thymidylate synthase (stopping conversion of dUMP to dTMP) which causes an imbalance which causes synthesis of DNA cleaving endonuclease.
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what is fluorouracil used for
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solid tumors like colon cancer and not for leukemias
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what phase does fluorouracil work in
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phase non-specific
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what are fluorouracil's major toxicity
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bone marrow suppression, oral and gastrointestinal mucositis
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what is mercaptopurine's mechanism of action
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purine analog that causes feedback inhibition of the first step in the purine biosynthetic pathway which leads to purine pool depletion. causes DNA strand breaks by incorporation into DNA. inhibition of RNA synthesis
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mercaptopurine's major toxicity
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bone marrow suppression
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what phase is mercaptopurine specific for
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s-phase specific
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what are some ways that cancer cells develop a resistance to mercaptopurine
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1. decreased HGPRT (hypoxanthin-guanine phosphoribosyl transferase - so doesn't incorporate anaolog into DNA annymore)
2. Altered HGPRT (so doesn't recognize analog) 3. Decreased transport into cells |
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what is mercaptopurine's major toxicity
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bone marrow suppression
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what paclitaxel mechanism
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bind to tubulin and alter normal formation of microtubulin and mitotic spindle. so don't get separation of chromo among other things, causing arrest in G2 or M
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what phase is paclitaxel specific for
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G2 or M
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what is paclitaxel's major toxicity
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neutropenia
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what is the basis of hormone/antihormone therapy for tumors
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some tumors are hormone sensitive so you chemically use a hormone antagonist or remove hormone secreting organ via surgery
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what are side effects like for hormones/antihormones compared to classical drugs
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they are less than classical drugs because they are more targetting for the tumor
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what types of breast cancer are susceptible to hormone/antihormone therapy
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50% of breast cancer patients have the ER+ cells which can be treated by hormone/antihor therapy. but 50% are ER- so they need classical chemotherapy
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what is the first line treatment for patients with ER+ cells
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antiestrogen Tamoxifen which binds to the ER and prevents estrogen from binding and inducing growth.
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what chemotherapy drugs do you give to patients with a negative ER/PR
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cyclophosphamide, doxorubicin, 5-fluorouracil
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Tamoxifen has
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mixed estrogenic/antiestrogenic effects. Anti on the breast. Estrogenic effects on bone and uterus.
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Tamoxifen adverse effects
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because of its estrogenic effects on the uterus, use of tamoxifen in post-menopausal patients is associated with increased incidence of endometrial cancer during long term treatment
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Raloxifene's mechanism of action
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mixed estrogenic/antiestrogenic effects. Estrogenic effects on bone and antiestrogenic effects on both the uterus and breast.
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because of tamoxifen's adverse effects what is going to happen to its use
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raloxifene may replace tamoxifen as the treatment of choice for ER+ metastatic breast cancer in postmenopausal patients
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what are the drugs of choice for treating post-menopausal ER+ patients
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aromase inhibitors like letrozole
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what is letrozole used for
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letrozole is used as adjuvant therapy in post-meno or to treat advanced metastic breast cancer in ost-menopausal patients
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what is letrozole's affect on endometrial cancer
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not associated with an increased incidence of endometrial cancer
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what do you do if you have a post-menopausal ER+ women who doesn't respond to tamoxifen or letrozole
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you give them fulvestrant (a estrogen receptor antagonist that acts by bind the ER receptor and inducing its down regulation
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how does tamoxifen affect the estrogen receptor
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it makes estrogen receptor into a partially active shape. Cells in the uterus, breast, and bone then have different mechanisms by which these activate transcription in the cells which leads to either an antiestrogenic or estrogenic effect.
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how does tamoxifen affect estrogen receptors in the bone and uterus vs breast tumor cells
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breast tumor cells have corepressors acting on the ER. Bone and uterus have coactivators acting on the ER
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other than increased risk of endometrial cancer in post-menopausal women what other side effects does tamoxifen have
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hot flashes, menstrual irregularities and skin rashes because of interference with normal receptor function
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describe letrozole's mechanism better
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letrozole and other aromatase inhibitors are testosterone analogs that compete for binding site on aromatase which converts androgens to estrogens. Premeno have lots of testosterone so competitive inhibition doesn't work. Postmeno have not a lot of testosterone so competitive inhibition does work
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what side effect does letrozole have on pre-menopausal women
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fetal toxicity
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what drugs are used in premenopausal women
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tamoxifen, raloxifene, and letrozole
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what drugs are used in postmeno women
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tamoxifen, raloxifene, letrozole, and fulvestrant
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what is the only not fetal toxic breast cancer drug
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tamoxifen
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which drugs increase clots in the postmeno
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tamoxifen and raloxifene
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how do you treat prostate cancer
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remove androgens to cause tumor regression or tumor stabilization via surgical removal of the testes or endocrine therapy
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DES does what
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Diethylstilbestrol (DES) is a drug, an orally active synthetic nonsteroidal estrogen that causes feedback inhibition of LH and FSH production = lower testicular androgen production
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aminoglutethimide does what
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prevents adrenal androgen production by inhibiting conversion of cholesterol to pregnenolone (Pregnenolone is a steroid hormone involved in the steroidogenesis of progesterone, mineralocorticoids, glucocorticoids, androgens, and estrogens)
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what does leuprolide do
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superagonist that inhibits LH and FSH secretion by desensitizing the GnRH receptor. Gonadotropin-releasing hormone (GnRH), also known as Luteinizing-hormone-releasing hormone (LHRH) and luliberin, is a tropic peptide hormone responsible for the release of FSH and LH from the anterior pituitary. GnRH is synthesized and released from neurons within the hypothalamus.
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what does flutamide do
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block the cellular effects of circulating androgens by blocking their binding to androgen receptor
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what does flutamide need to be given with
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flutamide decreases androgen mediated feedback inhibition of FSH and LH secretion by blocking androgens from binding to the anterior pituitary so leuprolide is given in conjunction with flutamide to prevent extra testosterone that would normally be produced
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what is prostate metastatic disease treated with
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paclitaxel and doxorubicin (if not hormone dependent prostate cancer) or endocrine therapy
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what is a possible major complication with aminoglutethimide
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its effects on P450 side chain cleavage prevents production of androgens, AND things like glucocorticicoids and mineral corticoids. Therefore you have to give hormone replacement therapy with aminoglutethimide.
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what is prednisone's mechanism
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synthetic glucocorticoid which functions through the GR (glucocorticoid receptor) and activates pro-apoptosis genes in lymphocytes. GCs are part of the feedback mechanism in the immune system that turns immune activity (inflammation) down
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what is prednisone used for
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used to treat B and T cell lymphomas generally. E.g. lymphocytic anemias, hodgkin's disease and non-hodgkin's lymphomas (In chronic lymphocytic leukemia (CLL), the DNA of a B cell is damaged, so that it can't produce antibodies. Additionally, B cells grow out of control and accumulate in the bone marrow and blood, where they crowd out healthy blood cells.)
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does prednisone have any effect on Bone marrow
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not myelosuppressive. doesn't suppress bone marrow so usually paired with drugs that don't have same side effect
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what is prednisone's main side effect
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acute tumor lysis syndrome (byproducts of cancerous WBC lysis): hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and acute renal failure
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what combo of drugs is used to treat cervical carcinoma
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cisplatin (DNA cross linker (renal side effects, Phase nonspecific), bleomycin (DNA strandbreaker (pulmonary toxicity, M/G2), methotrexate (antimetabolite inhibits nucleotide and protein biosynthesis (BMDepression and S phase specific)
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in general what are one of the major side effects for prostate and breast cancer therapy
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infertility for both men and women
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male infertility manifestations
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decreased testicular mass, decreased testosterone levels, azoospermia
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females infertilitity manifestations
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ovarian fibrosis, follicle destruction, decreased levels of estrogen, amenorrhea
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what chemotherapy drugs have high recurrent cancer risk
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DNA cross linkers and DNA damaging agents. E.g. cyclophosphamide
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what chemotherapy drugs have low recurrent cancer risks
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metabolic analogs. E.g. methotrexate, 5- fluorouracil
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what is CML
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chronic myelogenous leukemia is a cancer of bone marrow of white blood cells
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what causes CML
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chronic myelogenous leukemia is linked to a single molecular abnormality, the philadelphia chromosome: t(9;22) translocation, which causes a fusion between tyrosine kinase called abl and protein bcl
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what do you use to treat CML
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gleevac is an inhibitor of tyrosine kinases lik e Bcr-Abl, Kit and PDGF receptor by binding to the intracellular ATP binding site and blocks catalytic activity
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how effective is gleevec
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88% respond to treatment, it can be taken orally as a once a day pill, very mild side effects
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what do you have to worry about with gleevac
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potential drug interactions with substrates, inhibitors, and inducers of CYP3A4, CYPT2C9, CYP2D6
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what is gleevac contraindicated for
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pregnant women, breastfeeding women, or women who are going to be pregnnant because it interacts with kinases and growth factors
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what is herceptin used for
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it is a humanized monoclonal antibody aginst the p185(HER2) expressed on the surface of some breast cancer cells. It binds to it and so it blocks activity thru this growht factor receptor. It's used in combination with cyclophosphamide and doxorubicin to make their responses bigger
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what is the p185(HER2)?
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growth factor receptor. transmembrane receptor which is part of the EGFR (epidermal growth factor) family of receptors which has tyrosine kinase activity.
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can herceptin be used with pregos?
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it doesn't cross the placenta so it can be given to pregos
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what is herceptin's main adverse event
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small percentage of those who use it have cardiac failure manifesting as congestive heart failure and decreased left ventricular ejection fraction
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what is TYKERB used for?
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treatment of breast cancer. binds to the intracellular tyrosine kinase domains of EGFR type 1 (HER1) and EGFR type 2 (HER2). Functions as kinase inhibitior by preventing the binding of ATP
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what is TYKERB major side effect
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hepatotoxicity, fetal harm can occur when administered to a pregos (can cross placenta), can affect cardiac function (because it affects EGF receptor)
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