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25 Cards in this Set
- Front
- Back
what's the role of chemo in cancer treatment?
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for dealing with persistant/recurrent problems
adjuvant - breast cancer therapy after resection neoadjuvant - before surgery primary treatment regardless of stage...? |
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what are cancers with high cure rates? what's "cure" mean? what do they all have in common?
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cure = 5 years without recurrence.
ALL, choriocarcinoma, hodgkin's disease, osteogenic sarcoma, testicular carcinoma are all quite treatable, greater than 60% cure rate. these are all RAPIDLY DIVIDING CANCERS. |
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what general classes of drug resistance are there? mechanisms?
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primary - the tumor doesn't respond to therapy.
secondary - tumor develops resistance (tumor heterogeniety). mechanisms: 1. increased DNA repair by amping up topoisomerase 2. formation of trapping agents 3. change target enzymes 4. decreased activation of antimetabolites 5. increased drug eflux |
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chemotherapy - what are the principles about why it works?
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have selective toxicity - kill more tumor cells than healthy,
stop DNA synthesis more in tumor cells, and depend on healthy cells to be better at DNA repair than tumor cells. |
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growth fraction - what is it and what does it have to do with therapy?
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percentage of cells that are dividing - tumors with higher growth fractions are more easily treated.
also remember that earlier in a tumor, the growth fraction is high (it's in "log" phase, more divions = early) = better treatment possible |
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talk about the total kill concept:
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therapies kill a certain fraction of tumor cells each time it's given. even if it's 99.9% of tumor cells, if you're at 10^12 to 10^9, still have a billion cells.
hopefully you decrease WBC less than that. then wait for WBC's to recover, then hit the cancer again. If you kill 3 logs, then wait a couple weeks and the tumor recovers 1 log, you have a "net differential cell kill" of 2 logs. So, you need to repeat this process over and over again, even past the point where there's no detectable cancer. |
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how are cancer drug dosings different than other drugs?
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always give the maximum tolerated dose.
calculation not on weight, but on surface area. |
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what does the cell cycle have to do with drugs? in what part of the cycle are most tumor cells in? why is this interesting?
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like in regular tissue, most cancers are in G0. 15% dividing. if p53 muts, can get divide despite screwed up DNA and get resistant strains.
specific antimetabolites can attack specific stages in the cell division cycle. |
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generally, which drugs/classes attack those cells in the cell cycle specifically and which don't care?
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CCS (cell cycle specific) = antimetabolites, etoposide, bleomycin, vinca alkaloids, piclitaxel, docetaxel. Generally, those that attack Topoisomerase I or II, those that cause free radicals, etc.
CCNS - cell cycle non-specific = alkylating agents, anthracyclines, dactinomycin, campothecins, platinum analogues. Note that the campothecins do attack topoisomerase BUT are CCNS...so this is a violation of my rule |
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what are some philosophies of giving chemotherapy?
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combos to lower resistances. Methotrexate + Leucovorin, to help "rescue" GI/bone marrow.
give CCNS first to kill everything, tease G0's into replicating, then hit with the CCS. temporally divide drugs to inflict toxicities on different organ systems at different times. |
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How do the alkylating agents work? General side effects?
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they have a [NITROGEN MUSTARD MOIETY], which has the ability to bind to the [N7 position of Guanine], and results in [CROSS LINKING]. Note resistance can be built by increasing DNA repair, decreasing drug permeability, or extra glutathione that converts the drug.
see [MYELOSUPPRESSION, nausea and vomiting, GI toxicity, and allopecia]. |
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What are our general alkylating agents?
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cyclophosphamide, decarbazine, busulfan, mechlorethamine, melphalan, nitrosureas.
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Give some details about cyclophosphamide:
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all of this is important:
[broad spectrum.] [oral, no cytotoxic effects alone, has to be ACTIVATED by p450.] [first turned into 4-hydroxycyclophosphamide, then into aldophosphamide, then into acrolein/phosphoramide mustard. acrolein messes with the bladder, causing hemorrhagic cystitis - this is why you give MENSA at the same time. NOTE - [aldehyde dehydrogenase production by tumor cells, turns the active metabolites inactive = drug resistance] |
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dacarbazine details?
busulfan? what about mechlorethamine? what about melphalan? nitrosoureas? |
decarbazine:
[hodgkin's disease], SEVERE toxicity = [hepatic necrosis]. busulfan - out of fashion, used to be used for CML, replaced by gleevec. Lots of [MYELOSUPPRESSION] MeChlorEthAmine: [limited use] - used in MOPP - for hodgkins' disease, [CARCINOGENIC] = irony melphalan = [multiple myeloma] nitrosoureas = [brain tumors and mets], due to lipid solubility and blood brain barrier penetration. |
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which is the worst for hair? myelosuppression?
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hair loss = cyclophosphamide, along with the hemorrhagic cystitis
all cause myelosuppression, melphan and nitrosoureas are the worst. I'd also note that melphan is the only one that DOES NOT CAUSE HAIR LOSS. |
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I know i put the platinum analogues in another cardset, but why should they be here and what are typical problems?
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they're alkylating agents that cause DNA breaks. Beware NEPHRO and OTO toxcisity - these are the same as aminoglycosides, so DON'T USE WITH THEM!
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Antimetabolites! Which are they? How do they generally work?
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Cytarabine, 5-FloroUracil, Methotrexate, Thioguanine, and Mercaptopurine.
note that all have to be activated INTRACELLULARLY (inside the cancer cell). ALSO - add on Capecitabine and Gemcitabine: Capcitabine - breast colo/rectal, because it IS A PRODRUG OF 5-FU Gemcitabine - pancrease/bladder/nonsmall cell carcinoma - it inhibits RIBONUCLEOTIDE REDUCTASE, so no DNA. |
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How does 5-FU work?
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Remember that normally, DUMP uses THYMADILATE SYNTHASE to become TMP, using tetrahydrofolate as a cofactor.
think COLORECTAL and BREAST. 5-FU gets activated and becomes FdUMP - this forms a [ternary] complex with thymadilate synthase and the cofactor tetrohydrofolate - so the cells die a [thymadine-less death]. Also can get incorporated [into RNA and stop both DNA/RNA]. |
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WHat about cytarabine?
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[S phase specific!] - this is where AraCMP gets made. [inhibits DNApol].
used ONLY FOR [AML] = acute myelogenous leukemia. Also is [quickly metabolized] - so it has to be given by continuous infusion, due to S-phase specificity. |
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Methotrexate?
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Folic acid antagonist, targeting DiHydroFolateReductase - so it messes with [DNA, RNA, and PROTEINS].
has to be [activated to a polyglutemate derivative] first - this form is selectively held inside tumor cells. Known to get [resistance] due to decreased uptake, decrased polyglutemate function, and more DiHydroFolateReductase synthesis that makes MORE of the enzyme you're fighting. Don't forget that it's given with Leucovorin to help recover WBC's. |
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Thioguanine? Mercaptopurine?
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Thioguanine: [inhibits lots of enzymes in the purine nucleotide synthesis pathway.]
Mercaptopurine - [used for ALL and AML] |
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What's MOPP used for? What's another combination used in this disease?
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MOPP is for hodgkin's.
it's mechlorethamine, vinclastine, procarbazine, and prendosone. also can use ABVD: Doxorubicin, bleomycin, vinblastine, decarbazine. |
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what is CHOP used for? what's an alternative cocktail?
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CHOP is used for NHL.
Cyclophosphamide, vincristine, prenosone, and DOXORUBICIN (weird one - for hydroxydoxorubinc). can also use BACOP: Bleomycin, doxorubicin, cyclophosphamide, vinchristine, and prendosone. |
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what combos do we use to treat testicular cancer?
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PEB and PVB:
PEB: Platinums, etoposide, bleomycin. PVB: platinums, vinblastine, bleomycin. Less favored now. Vinblastine's mostly used for KS these days. |
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what combos do you use for breast cancer?
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CMF and CAF.
CMF = cyclophosphamide, methotrexate, 5-fu. CAF = cyclophosphamide, doxorubicin, and 5-fu. Don't forget that you use Leukovorin with 5-FU and methotrexate, usually. |