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antineoplastics I
cmbm exam V
56
Chemistry
Graduate
02/16/2010

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Term
what is 5-flouro-uracil 5-FU used for? is it complexed w/anything?
Definition
5-FU is very commonly used in solid tumors. it is complexed with regimine (and other anti-neoplastic agents)
Term
what is cytarabine used for? what is it?
Definition
leukemias, lymphomas - it is a purine analogue that is incorporated into DNA and disrupts synthesis
Term
what are alkylating agents used for?
Definition
solid tumors and lymphomas
Term
what do platinum analogues do?
Definition
form adducts w/DNA
Term
what is asparginase? how does it work?
Definition
breaks down asparginase (cancer cells don't have asparagine synthetase and get it from the diet)
Term
what is placitaxel? when is it used, what does it do?
Definition
an alkaloid that is used in solid tumors, it inhibits cell division in M phase
Term
what are protein tyrosine kinase inhibitors?
Definition
protein tyrosine kinase inhibitors such as herceptin have a specific protein which can be targeted with an antibody
Term
what are topoisomerase inhibitors used for? what is an example of one?
Definition
lymphomas. etoposide is an example of one used for lymphomas, doxorubicin forms free radicals to break DNA but has cardio toxicities
Term
what is methotrexate used for? what cells can it affect other than tumor cells?
Definition
methotrexate is active against solid tumors by inhibiting dihydrofolate reductase (blocks folic acid production needed for DNA synthesis). other fast growing cells besides tumor cells such as bone marrow, hair, GI epithelium, and mucosal are also affected by methotrexate
Term
what is 6-mercaptopurine? what is it used for?
Definition
this adosine analogue is incorporated as a mercaptoadosine adduct and confuses DNA polymerase. 6-mercaptopurine is used for lymphomas and & leukemias - NOT solid tumors
Term
what is the implication of the log-kill hypothesis?
Definition
it takes several cycles to get the level of cancer cells down to zero (from 10^9 -> 10^8 is one log kill) so early prevention helps reduce this necessity, along with sx and radiation
Term
what is the primary treatment for hematologic and diffuse cancers (eg leukemias?)
Definition
chemotherapy
Term
when is chemotherapy used?
Definition
chemotherapy can be used as adjuvant therapy after surgery and radiation of solid tumors, initial therapy before surgery to downstage breast cancer, as chemoprotection in high risk individuals
Term
what is selective toxicity?
Definition
aiming directly at cancer modality (though some normal cells will be affected), monoclonal antibodies can are better with this or working with tyrosine kinase
Term
what chemotherapy agents target the M (mitotic) phase?
Definition
alkaloids such as vinicristine and vinblastine
Term
what antimetabolits inhibit the S phase?
Definition
methotrexate and 5-FU
Term
what chemo drugs target the G2 phase?
Definition
etoposide and bleomycin
Term
what drugs are non phase specific?
Definition
alkylating drugs, nitrosources, antitumor antibx, procarbazine, cisplatin, and dacarbazine
Term
what are common toxicities of chemotherapy?
Definition
anemia, bone marrow toxicity, immune suppression, GI tract damage b/c of fast epithelial overturn (ulceration/decreased absorption=nutritional strain), loss of hair, sores, sterility, nausea, vomiting, possibility of induced cancer
Term
how can drug resistance to chemotherapy occur?
Definition
decreased permeation/increased drug efflux (ex P-glycoprotein in methotrexate and vinicristine), increased intracellular thiol conc., increased activity of DNA repair pathways, and increased rates of metabolism
Term
what is p-glycoprotein?
Definition
a multidrug resistance gene expressed in lots of cancer cells
Term
what are the nitrogen mustards/DNA alkylating agents? how do they work? what are bifunctional alkylating agents?
Definition
cyclophosphamide (prototype), mechlorethamine, ifosamide, chlorambucil. they attach a methyl modality to DNA molecules (guanine is the preference base) and keep it from replicating appropriately. bifunctional alkylating agents can also cause interstrand cross-linking. they are good for solid tumors b/c they are very harsh on DNA so when they do divide, they don't go anywhere
Term
when is meclorethamine used? ADRs?
Definition
meclorethamine is used as a component of MOPP in tx of hodgkins disease, it causes injection site pain, is highly reactive with other drugs and can cause myelosuppression
Term
how is cyclophosphamide metabolized?
Definition
cyclophosphamide is not toxic on its own, it is processed by cytochrome P450 to make toxic metabolites such as aldophosphamide. cancer cells dont have the enzymes to inactivate aldophosphamide, so aldophosphamide becomes acrolein which is cytotoxic (however, not the primary anti tumor species) and can cause hemorrhagic cystitis** and phosphoramide mustard which is the primary antitumor agent.
Term
when is cyclophosphamide used?
Definition
is used for both lymphomas and solid tumors
Term
what kind of drug is cyclophosphamide considered? why is mesna disulfide/predrug hydration coadministered?
Definition
a prodrug. disulfide/predrug hydration coadministered is given to lessen hemorrhagic cystitis from acrolein
Term
what is different about ifosfamide?
Definition
ifosfamide is similar to cyclophosphamide but takes longer/need larger doses to get to ifosfamide mustard.
Term
what is significant about chlorambucil?
Definition
chlorambucil is an alkylating agent that has good bioavailability, is well tolerated on a daily basis and has lower toxicity that can be more easily reversed
Term
what is is chronic myeloid leukemia (CML), and what drugs are used for it?
Definition
CML is a BCR-ABL translocation (phila chr) causing unregulated tyrosine kinase -> unregualted WBCs. busulfan (sulfonate alkylator) was used, not imatinib mesylate is used, which as less side effects and has a higher CML selectivity by inhibiting a portion of the defective enzyme (allows pts to live more comfortably)
Term
what is carmustine? what is it used in? what is an ADR?
Definition
carmustine is a nitrosourea alkylating agent that is highly lipid soluble, and is used in treating hodgkins/non-hodgkins lymphomas, brain cancers, and *meningial leukemias* by causing cross-linking, usually on guanine. it can cause cancer eventually
Term
how do platinum salts such as cisplatin work? ADRs? when are they used?
Definition
platinum salts form covalent intrastrand cross linking of dsDNA (alkylation), keeping it from necessary separation in replication via DNA polymerase. ADRs include nephrotoxicity (monitor creatinine clearance). they are used in solid tumors. ototoxicity/peripheral neuropathy.
Term
what is FOLFOX?
Definition
FOLFOX is a combination of 5-flourouracil and leukovorin (leukovorin is essentially folic acid. this will supplement body with some folate so you do not have as much bone marrow suppression)
Term
what are anthracyclines?
Definition
tetracycline antibx including doxorubicin (most important), daunorubicin, mitoanrone, idarubicin
Term
what is doxorubicin used for? ADRs?
Definition
doxorubicin is widely used for lymphomas, leukemias, and solid tumors. it inhibits topoisomerase II and produces free radicals and is used in a high dose initially with synergistic agents to minimize the # cycles, due to high toxicity, esp w/potential irreverible CHF (blood markers should be monitored)
Term
what is dexrazoxane?
Definition
an agent coadministered with doxorubicin that chelates Fe to prevent iron-mediated free radical generation - reduces cardiotoxicity. this shows how good doxorubicin is for killing cancer if there are drugs being developed to keep its toxicity down
Term
what does bleomycin do? when is it used? ADR?
Definition
bleomycin is an antibiotic that causes DNA strand breaks (formes Fe free radicals) and is used in hodgkins as well as certain testicular/lung CAs. it is associated with dose-related pulmonary fibrosis.
Term
what are examples of antimetabolites?
Definition
methotrexate, 5-FU, mercaptopurine, and cytarabine
Term
what is the M/A for methotrexate (MTX)?
Definition
methotrexate inhibits dihydrofolate reductase (and thymidylate synthase) b/c is is very close to folic acid in structure and competes with it. it exists in a *polyglutamated* form in cells which is too bulky to leave, and has to be eliminated in 2 phases by the renal system.
Term
what is MTX used for?
Definition
MTX is indicated for ALL, NHL, solid tumors as well as RA and psoriasis
Term
what is leucovorin?
Definition
activated folate administered with high dose methotrexate (like w/choriocarcinoma) to avoid severe bone marrow depression
Term
what is significant about methotrexate being a weak acid?
Definition
if MTX levels remain high, nephrotoxicity can result, this can be avoided by alkalinizing urine to ionize and eliminate MTX
Term
what are ADRs for MTX?
Definition
bone marrow suppression, ulcers, and pulmonary fibrosis (not as bad as bleomycin)
Term
what are some drug-drug interactions w/MTX?
Definition
antibx such as sulfonamides/tetracyclines can cause increased toxicity (or other highly plasma protein bound drugs). drugs that compete for tubular secretion such as PCN/cephs, or reduce renal flow (NSAIDs) and keep MTX levels too high. high MTX levels can be adjusted with leukovorin.
Term
what drugs can inhibit both thymidylate synthase?
Definition
methotrexate and 5-FU
Term
what does 5-flourouracil do? when is it used? ADRs?
Definition
5-FU is activated to FdUMP which complexes with tetrahydrofolate to inhibit thymidine synthetase, stopping DNA synthesis. FdUMP also causes miscoding of RNA, making protein translation difficult. is used in solid tumors esp the colon. it can cause bone marrow suppression.
Term
what is mercaptopurine?
Definition
a purine antimetabolite that mimics adenine and causes misreading in DNA, leading to miscoding and faulty translation.
Term
what is cytarabine?
Definition
a pyrimidine that is incorporated and activated into CTP which inhibits DNA polymerase - it is an S phase specific metabolite.
Term
why are purines and pyrimidines analogues good for leukemias and lymphomas?
Definition
because they have rapidly dividing cells
Term
are alkylating agents cell cycle specific agents?
Definition
no
Term
are antimetabolites cell specific agents?
Definition
yes, for S phase
Term
what kind of DNA do alkylators damage?
Definition
preformed DNA via interstrand crosslinks
Term
what kind of DNA do antimetabolites damage?
Definition
new DNA (why they are good for leukemias and lymphomas)
Term
what level of proliferation do alkylators target?
Definition
rapid and slow G0 proliferating cells
Term
what level of proliferation do antimetabolites target?
Definition
just rapidly proliferating cells
Term
of alkylators and antimetabolites, which is more likely to kill BM cells or cause secondary lymphomas/leukemias?
Definition
antimetabolites
Term
of alkylators and antimetabolites, which is more likely to have larger carcinogenic, tetragenic and mutagenic properties?
Definition
alkylators
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