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25 Cards in this Set

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what's the role of chemo in cancer treatment?
for dealing with persistant/recurrent problems

adjuvant - breast cancer therapy after resection
neoadjuvant - before surgery

primary treatment regardless of stage...?
what are cancers with high cure rates? what's "cure" mean? what do they all have in common?
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.
what general classes of drug resistance are there? mechanisms?
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
chemotherapy - what are the principles about why it works?
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.
growth fraction - what is it and what does it have to do with therapy?
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
talk about the total kill concept:
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.
how are cancer drug dosings different than other drugs?
always give the maximum tolerated dose.

calculation not on weight, but on surface area.
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?
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.
generally, which drugs/classes attack those cells in the cell cycle specifically and which don't care?
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
what are some philosophies of giving chemotherapy?
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.
How do the alkylating agents work? General side effects?
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].
What are our general alkylating agents?
cyclophosphamide, decarbazine, busulfan, mechlorethamine, melphalan, nitrosureas.
Give some details about cyclophosphamide:
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]
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.
which is the worst for hair? myelosuppression?
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.
I know i put the platinum analogues in another cardset, but why should they be here and what are typical problems?
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!
Antimetabolites! Which are they? How do they generally work?
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.
How does 5-FU work?
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].
WHat about cytarabine?
[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.
Methotrexate?
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.
Thioguanine? Mercaptopurine?
Thioguanine: [inhibits lots of enzymes in the purine nucleotide synthesis pathway.]

Mercaptopurine - [used for ALL and AML]
What's MOPP used for? What's another combination used in this disease?
MOPP is for hodgkin's.

it's mechlorethamine, vinclastine, procarbazine, and prendosone.

also can use ABVD:
Doxorubicin, bleomycin, vinblastine, decarbazine.
what is CHOP used for? what's an alternative cocktail?
CHOP is used for NHL.
Cyclophosphamide, vincristine, prenosone, and DOXORUBICIN (weird one - for hydroxydoxorubinc).

can also use BACOP:
Bleomycin, doxorubicin, cyclophosphamide, vinchristine, and prendosone.
what combos do we use to treat testicular cancer?
PEB and PVB:

PEB:
Platinums, etoposide, bleomycin.

PVB: platinums, vinblastine, bleomycin. Less favored now. Vinblastine's mostly used for KS these days.
what combos do you use for breast cancer?
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.