Kaplan Section 8 - Cancer
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| What is the log-kill hypothesis? | Anti-cancer drugs kill a fixed percentage of tumor cells (first order kinetics), not a fixed number per time. This is the rationale for drug combinations.
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| T or F: Cytotoxic drugs are more effective against tumors that have a low growth fraction. | FALSE. These drugs are more effective against tumors and cells that have a high growth fraction (cell POPULATIONS with a large percentage that is rapidly dividing -- e.g. bone marrow or active tumor cells).
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| What does it mean that a drug is cell-cycle specific? | Drugs that act on cells that are actively proliferating.
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| Name the drugs that are S-phase specific. | 66-CHEM: 6-mercaptopurine, 6-thioguanine, cytarabine, hydroxyurea, etoposide, methotrexate (cytotoxic to lymphocytes, used for RA)
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| Name the drugs that are G2-phase specific. | Bleomycin
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| Name the drugs that are M-phase specific. | VPV (looks like upside down M): Vinblastine, Pacilitaxel, Vincristine
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| Name the drugs that are G0-phase specific. | 1. alkylating agents, 2. antitumor abx, 3. nitrosoureas, 4. decarbazine, 5. cisplatin
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| What is the mechanism of methotrexate? | anti-metabolite: inhib DHF reductase in S phase of cell cycle --> cells can't make tetrahydrofolic acid (active form of folate) from dihydrofolic acid --> folate def --> can't make Thymine, needed for rapid cell division --> can't divide; cytotoxic to lym
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| How does the body develop resistance to methotrexate? | 1. change in binding affinity of DHF reductase to the drug, 2. cells won't let as much drug accumulate via either increased expression of transporters (to get drug out) or decreased permeability (won't let as much in)
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| What diseases would you use methotrexate for? | 1. leukemias, 2. lymphomas, 3. breast cancer, 4. RA, 5. psoriasis
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| Adverse effects of methotrexate | 1. bone marrow suppression, 2. mucositis, 3. crystalluria,
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| What is leucovorin rescue? | Leucovorin is a derivative of tetrahydrofolic acid whose synthesis does not depend on DHF reductase --> some thymine can still be made --> purine synthesis continues --> healthy cells can keep on dividing. Prescribed with methotrexate to rescue healthy c
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| What is cyclophosphamide? | Alkylating agent - works in G0 Phase. A Prodrug that is converted to active forms in the liver. Forms DNA crosslinks between and within DNA strands at guanine N-7 positions --> dysfxnal DNA --> cell death.
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| What would you use cyclophosphamide for? | 1. Non-Hodgkin's lymphoma, 2. ovarian cancer, 3. breast cancer, 4. neuroblastoma
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| What are the adverse effects of cyclophosphamide? | 1. bone marrow suppression, 2. mucositis, 3. hemorrhagic cystitis, 4. hepatotoxicity (high dose)
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| What is hemorrhagic cystitis and with what drug do you get it? | sudden onset of hematuria (blood in urine) combined with bladder pain and irritative bladder symptoms
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| Why do pts get hemorrhagic cystitis on cyclophosphamide? | cyclosphosphamide --> broken down into acrolein --> excreted through bladder --> acrolein is toxic to bladder epithelium --> ulceration --> bleeding; aldehyde dehydrogenase breaks down the drug into other metabolites that are NOT as toxic as acrolein (pro
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| If on cyclophosphamide, how to prevent hemorrhagic cystitis? | Use Mesna (traps acrolein) or aggressive hydration for prophylaxis
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| What is Cisplatin? | Alkylating agent - works in G0 Phase. Crosslinks DNA strands, similar to cyclophosphamide.
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| How does the body develop resistance to Cisplating? | 1. Traps the drug, 2. increases cell's ability to repair the damaged DNA.
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| What would you use Cisplatin for? | 1.Testicular CA, 2. Ovarian CA, 3. Bladder CA, 4. Lung CA
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| Adverse effects of Cisplatin | 1. Nausea, 2. Vomiting (use Odansetron), 3. Nephrotoxicity (use Amifostine), 4. Neurotoxicity (deafness)
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| What is Doxorubicin? | 1. An intercalator --> inhibition of macromolecular biosynthesis --> inhibits the progression of the enzyme topoisomerase II, which unwinds DNA for transcription --> stabilizes the topoisomerase II complex after it has broken the DNA chain for replication
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| What would you use Doxorubicin for? | 1. Hodgkin's lymphoma (ABVD, doxorubicin = adriamycin), 2. breast ca, 3. endometrial ca, 4. lung ca, 5. ovarian ca
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| Adverse effects of doxorubicin | 1. bone marrow suppression, 2. delayed CHF, 3. alopecia, 4. vesicant (causes blistering), 5. radiation "recall"
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| What is radiation recall? | severe skin reaction that occurs when chemotherapy drugs (doxorubicin) administered during or soon after radiation treatment. The rash appears like a severe sun burn. Treatment = corticosteroids to reduce inflammation.
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| What is dexrazoxane? | A drug that protects from the cardiotoxic radical-formation effects of doxorubicin. It chelates iron and prevents the formation of free radicals.
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| What is the mechanism of 6 mercaptopurine? | S-phase anti-metabolite; Inhibits purine synthesis; activated by HGPR transferase, an enzyme in purine metabolism
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| How does the body develop resistance to 6-mercaptopurine? | form enzymes that inactivate the drug
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| What would you use 6-mercaptopurine for? | 1. Acute lymphocytic leukemia, 2. immunosuppression
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| What is azathioprine? | It's the prodrug that is metabolized to become 6-mercaptopurine
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| What are the adverse effects of 6-mercaptopurine? | 1. bone marrow suppression, 2. hepatotoxicity (jaundice, necrosis), 3. GI distress
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| How does the body develop resistance to azathioprine? | Reduced activation of the prodrug.
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| What is vincristine? | Decreases microtubule polymerization (Vincristine binds to tubulin dimers, inhibiting assembly of microtubule structures) --> arrests mitosis (M phase) at metaphase ==> affect all rapidly dividing cell types, including the epithelium and bone marrow.
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| What is vinblastine? | Decreases microtubule polymerization (Vinblastine binds to tubulin --> inhibiting assembly of microtubule structures) --> mitotic spindle and kinetochore can't form --> chromosomes can't separate during anaphase --> arrests mitosis (M phase) at anaphase.
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| What diseases would you use vinblastine for? | 1. Hodgkin's lymphoma (ABVD, V = vinblastine), 2. testicular ca, 3.kaposi's sarcoma
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| What diseases would you use vincristine for? | 1. Hodgkin's lymphoma (MOPP), 2. leukemia, 3.Wilms' tumor (tumor of kidneys)
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| Adverse effects of vinblastine. | 1. bone marrow suppression, 2. GI distress, 3. alopecia
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| Adverse effects of vincristine. | neurotoxic
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| What is bleomycin? | Anti-cancer drug. Complexing with Fe and O2 --> induce breaks in the DNA strand (G2 Phase)
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| What would you use bleomycin for? | 1. Hodgkin's lymphoma (ABVD, B = bleomycin), 2. testicular ca, 3. head ca, 4. neck ca, 5. skin ca
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| Adverse effects of bleomycin | 1. pneumonitis, 2. pulmonary fibrosis, 3. mucocutaneous rxns (blisters), 4. alopecia, 5. hypersensitivity
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| What is procarbazine? | Alkylating agent - works in G0 Phase.
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| How does the body develop resistance to alkylating agents? | 1. decreased drug accumulation (by inc transports to get it out of cell OR by dec permeability to allow less in), 2. Production of chemicals that "trap" the drug
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| For what disease would you use Procarbazine? | 1. Hodgkin's lymphoma (MOPP)
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| What are the adverse effects of procarbazine? | 1. bone marrow suppression, 2. pulmonary toxicity, 3. hemolysis, 4. neurotoxicity, 5. leukemogenic
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| What is 5-fluorouracil? | Anti-cancer drug, anti-metabolite. Bioactivated --> inhibit thymidylate synthetase --> halt pyrimidine synthesis (can't make thymine)
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| How does the body develop resistance to 5-fluorouracil? | form enzymes that inactivate the drug
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| What would you use 5-fluorouracil for? | 1. ovarian ca 2. Breast ca, 3. head ca, 4. neck ca, 5. basal cell ca, 6. keratoses
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| What are the adverse effects of 5-fluorouracil? | 1. bone marrow suppression, 2. GI distress, 3. alopecia
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| What is 5-fluorouracil bioactivated to in the body? | 5-FdUMP
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| What is Flucytosine? | Like 5-fluorouracil, Flucytosine is bioactivated to form 5-FdUMP, which also inhibits thymidylate synthase --> can't make thymine --> halt DNA synthesis --> cell death
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| What parts of the body are most sensitive to cytotoxic cancer drugs? | rapidly proliferating cells: bone marrow, GI tract epithelium (mucosa), hair follicles, gonads
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| What is the cancer drug toxicity that is dose-limiting? | bone marrow suppression
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| Which drugs are particularly toxic to the kidneys? | Cisplatin and methotrexate
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| Which drugs relatively spares the bone marrow? | Cisplatin, Bleomycin, Vincristine, Asparaginase (B-VAC)
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| Which drugs are particularly toxic to the liver? | 6-Mercaptopurine, Busulfan, Cyclophosphamide
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| Which drugs are particularly toxic to the lungs? | Bleomycin, Busulfan, Procarbazine
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| Which drugs are particularly toxic to the heart? | Doxorubicin, daunorubicin
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| Which drugs are particularly toxic to the nerves? | Vincristine, Cisplatin, Paclitaxel
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| Which drugs are particularly immunosuppressive? | Cyclophosphamide, Cytarabine, Dactinomycin, Methotrexate
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| Which drug causes hemorrhagic cystitis? | cyclophosphamide
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| Which drug causes secondary leukemia? | Procarbazine
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| Which drug causes pancreatitis? | Asparaginase
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