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59 Cards in this Set
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What is a general MOA of antimetabolites?
Name 3 main classes of antimetabolites. Name all the agents in each class |
intereferes with nucleic acid synthesis
Folate Antagonist - methotrexate, pemetrexed Pyrimidine analogs - Fluorouracil (5FU), Capecitabine, Cytarabine (ara-C), and Gemcitabine Purine analogs - 6-mercaptopurine, thioguanine, pentostatin, cladrbine, fludarabine |
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Methotrexate
Class MOA Pharmacokinetics resistance resistance adverse reactions |
antimetabolite; folate antagonist
inhibits DHFR enzyme (DHF --> THF) Oral administration is rapid but often incomplete renal excretion Resistance 1. decreased transport into cells 2. production of altered DHFR 3. increased amt of DHFR 4. increased expression of MRP protein |
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Leucovorin
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folic acid surrogate
often administered with methotrexate to rescue normal cells |
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Pemetrexed
Class MOA Pharmacokinetics adverse reactions |
folate antagonists
inhibits thymidylate syntase and DHFR; converted polyglutamates Pharmacokinetics - similar to methotrexate; |
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5FU (fluorouracil)
class MOA Phamacokinetics |
pyrimidine analogs
thymidylate synthase inhibitor; 5FUTP incorporation of RNA --> error in transcription Pharmacokinetics - rapidly distribution and extensive metabolism |
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Cytarabine (Ara-C)
Class MOA Pharmacokinetics |
pyrimidine analogs
Competitive inhibitor of DNA polymerase hepatic metabolism and renal clearnace |
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Capecitabine
Class MOA Pharmacokinetics |
pyrimidine analog (same as 5FU)
same axns as 5FU - inhibition of thymidylate synthase and 5FUTP incorporation of RNA Oral administration |
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Gemcitabine
Class MOA |
pyrimidine analog (flourinated deoxycytidine)
inhibits DNA polymerase |
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6-mercaptopurine
Class MOA Pharmacokinetics drug interaction |
purine analog
IMPDH inhibition oral administration but poor absorption conversion via HGPRT interaction with allopurinol (gout drug) - 50% dosage for allopurinol users |
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Thioguanine
Class MOA Pharmacokinetics |
Purine analog
IMPDH inhibition Oral administratoin renal elimination conversion via HGPRT |
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Pentostatin
Class MOA |
purine analogs
deoxyadenosine analog potent inhibitor of adenosine deaminase (involved in purine metabolism) |
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Cladribine
Class MOA Pharmacokinetics |
Purine analog (chlorinated adenine)
inhibition of DNA polymerase adenosine deaminase resistant IV only rapid plasma clearance |
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fludarabine
Class MOA Pharmacokinetics |
purine analogs (flourinated adenine)
inhibition of DNA polymerase oral and IV admin. |
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What is the MOA of alkylating agents?
What are 2 types of alkylating agents? MOA? |
form intrastand and interstrand cross-links of guanine bases in DNA --> interferes with DNA replication
Monofunctional - 1 reactive group; single strand break via depurination Bifunctional - 2 reactive groups; form corss-links b/t DNA strands |
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Name 4 drug classes of alkylating agents.
Name agents of each class. |
Nitrogen mustards - mecholorethamine, cyclophosphamide, ifosfamide (melphalan, chlorambucil)
Nitrosoureas - carmustine and lumstine Platinum compounds - cisplatin, carboplatin, oxaliplatin others - non-classical alkylating agents (Dacarbazine, procarbazine, temozolamide), alkyl sulfonates (busulfan), bendamustine |
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Mechlorethamine
Class MOA Pharmacokinetics adverse rxns |
alkylating agent - nitrogen mustards
bifunctional alkylator IV only highly unstable and short t1/2 vesicant |
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Cyclophosphamide
Class MOA Pharmacokinetics special precautions |
alkylating agent; nitrogen mustard
bifunctional alkylating agent conversion via Hepatic P-450 IV or oral dose adjustment for both hepatic and renal toxicities hemorrhagic cystitis - administer with Mesna for prevention |
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Ifosfamide
Class MOA Pharmacokinetics special precaution |
alkylating agent; nitrogen mustard
bifunctional alkylating agent conversion via Hepatic P-450 IV or oral dose adjustment for both hepatic and renal toxicities hemorrhagic cystitis - administer with Mesna for prevention |
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Carmustine (BCNU)
Class MOA Pharmacokinetics |
alkylating agent; nitrosourea
alkylation of DNA IV only crosses BBB requires bioactivation |
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Lumustine (CCNU)
Class MOA Pharmacokinetics |
nitrosoureas; alkylating agent
alkylation of DNA Oral only Crosses BBB |
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Bendamustine
Class MOA Pharmacokinetics |
alkylating agent; bifunctional mechlorethamine derivative
purine analog and alkylator hybrid activate against both quiescent and dividing cells IV infusion |
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Busulfan
Class MOA Pharmacokinetics |
alkylating agent; alkyl sufonates
bifunctional alkylating agent Orally effective |
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dacarbazine
Class MOA Pharmacokinetics resistance |
non-classical alkylating agent
purine analog alkylation interact with SH group hepatic metabolism via P450 vesicant resistance via repair of guanine bases by ganine )-alkyl transferase |
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Procarbazine
Class MOA Pharmacokinetics |
nonclassical alkylating agents
alkylation inhibits incorporation of small DNA precursors, RNA/protein synthesis Oral drug S-phase specific corsses BBB |
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Temozolamide
Class MOA Pharmacokinetics |
nonclassical alkylating agents
similar to dacarbazine: purine analog alkylating agent interaction with SH group Oral administration spontaneous activation |
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cisplatin
Class MOA Pharmacokinetics Resistance rescue |
platinum compounds; alkylating
intrastrand ad interstand cross-link with DNA inorganic water soluble Only IV resistance via mismatch repair proteins rescue via amifostine to reduce renal toxicity with repeated cisplatin therapy |
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3 modes of action of platinum compounds??
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forms interstrand cross-link
monofunctionally bound intrastrand cross-link |
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carboplatin and oxaliplatin
Class MOA Pharmacokinetics |
platinum compounds/ alkylating
interstrand DNA cross-links Oxaliplatin - effective in mismatch repair deficient tumors |
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Name 4 topoisomerase inhibitors.
What is the function of topoisomerase? |
Topo I inhibitors - Topotecan, Irinotecan
Topo II inhibitors - Etoposide (VP16), Teniposide (VM-26) topoisomerase - cleave and unwind DNA to release torsional stress |
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Topotecan
Class MOA Pharmacokinetics Resistance |
Topo I inhibitor; camptothecan analogs
Topo I inhibition --> DNA strand breakage IV only higher CNS penetration compared with other camptothecins MRP transporters decreased expression or mutation of topo I |
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Irinotecan
Class MOA Pharmacokinetics Resistance |
Topo I inhibitor/ camptothecan analog
inhibition of topo I --> DNA strand breakage converted to activate SN-38 (only small percentage) in liver Dose reduction required for liver dysfunction Active in S phase elimination via bile and feces |
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Etoposide (VP16)
Class MOA Pharmacokinetics resistance toxicity |
Topo II inhibitor; epidophyllotoxins
Topo II inhibition --> DNA strand breakage Oral admin. active in late S and G2 phases Amplificaiton of MDR-1 gene mutation or decreased expression of topo II p53 mutations chromosomal translocations associated --> induced secondary malignancies |
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Teniposide (VM26)
Class MOA Pharmacokinetics |
Topo II inhibitor/ epipodophyllotoxins
inhibition of topo II --> DNA strand breakage injection Same resistance as etoposide MDR amplification mutation/decreased expression of topo II |
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names of Anthracyclines antibiotics?
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Doxorubicin (adriamycin)
Daunorubicin Epirubicin Idarubicin |
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Anthracyclines-antibiotics
MOA (4) Pharmacokinetics toxicity resistance |
non-covalent DNA binding drugs
1. inhibits topo II --> DNA strand breakage 2. intercalation within DNA --> blocks synthesis of DNA and RNA 3. binding to cellular membrane --> alter fluidity and ion transport 4. generation of free radicals poor penetration into CNA liver metabolism excreted in bile active in G2 phase Cardiotoxicity via free radical formation Resistance 1. MDR 2. glutathione oxdiase activity 3. decreased topo II |
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Antitumor antibiotics agents (3) ??
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bleomycin
dactinomycin (actinomycin-D) mitomycin C |
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Bleomycin
Class MOA toxicity |
antibiotics from Streptomyces verticillus
chelates Fe --> binds to DNA --> DNA fragmentation pulmonary toxicity |
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Dactinomycin (actinomycin-D)
Class MOA |
antibiotics
Intercalation b/t adjacent G-C base pairs --> inhibits RNA synthesis |
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Mitomycin C
Class MOA |
bifunctional or trifunctional alkylating agent; antibiotics
metabolic activation --> alkylating agent --> crosslinks DNA and single strand breaks of DNA |
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Vinka alkaloids
drug agents (3) MOA phamacokinetics adverse reactions special precautions drug resistance |
Vincristine, Vinblastine, Vinorebine
MOA - inhibit polymerization of tubulin --> inhibition of mitosis Given IV hepatic clearance specific for M phase Vincristine - peripheral neuropathy (dose-limiting) Vinblastine - vesicant; less neurtoxicity Vinorelbine - mildest neurotoxicity Vincristine + vinblastine combo fatal if given intrathecally drug resistance 1. P-glycoprotein, a membrane efflux pump 2. MDR 3. mutations in tubulin |
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Taxanes
agents (2) MOA phamacokinetics resistance |
Paclitaxel (taxol)
Docetaxel (semisynthetic taxane) inhibits disassembly of microtubule --> inhibits mitosis and cell division G2 and M phase specific Resistance via 1. MDR 2. mutants in tubulin that prevents binding |
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Epothilones
agent (1) MOA clinical use |
Ixabepilone (semi-synthetic analog of epothilone B)
block microtubule disassembly effective in drug resistance tumors (overexpression of P-glycoproteins or tubulin mutations) |
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L-asparaginase
MOA |
tumor cells require asparagines for rapid, malignant growth
converts asparagein tinto aspartic acid |
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Arsenic trioxide
MOA |
Induction of apoptosis via degradation of the fusion protien PML-RARalpha
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Advantages (4) and disadvantages (3) of tumor specific monoclonal antibodies
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advantages
1. might elicit immune-mediated cytotoxicity 2. might induce receptor internalization and degradation 3. inhibit signaling activation 4. long half-lives disadvantages 1. IV admin 2. does not bind with ECD truncation 3. saturation of receptors and high conc. ligand might inhibit antibody binding |
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Rituximab
Class MOA clinical uses |
tumor specific monoclonal antibodies
targets all CD20-positive B lymphocytes --> elimination of B cells by ADCC or CDC apoptosis CD20 is a specific marker for pre-B and mature B lymphocytes B cell non-Hodgkin's lymphoma B cell leukemia |
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Tositumomab
Class MOA clinical use |
Radiolabeled monoclonal antibody
targets CD20 positive B cells for tumors resistant to Rituximab and tumors relapsed following chemotherapy |
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Gemtuzumab
Class MOA Clinical uses |
monoclonal antibody for CD33
CD33 islinked to cytotoxic agnet caliheamicin CD33 is present on the surface of leukemic blasts --> apoptosis for acute myeloid leukemia |
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Name 2 drugs that inhibit EGFR tyrosine kinase intracellularly.
Route of administration? clinical uses? |
Gefitinib
Erlotinib Oral admin. non-small cell lung cancer, pancreatic cancer (Erlotinib) |
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Name 3 monoclonal antibody agents that inhibit EGFR extracellularly.
Which one is directed against HER2 (ErbB2)? Clinical use? |
Cetauximab
Panitumumab Trastuzumab - against Her2; Her2 positive metastatic breast cancer |
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Name 2 drugs that inhibition BCR-ABl kinase intracellularly.
Route of admin? Clinical use (optional)? |
Imatinib
Nilotinib Oral admin. Chronic myeloid leukemia (CML) |
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Dasatinib
class MOA Pharmacokinetics Clinical use (optional) |
intracellular signaling antagonist
dual specific SRC/BCR-ABL kinase inhibitor Oral admin Imatinib resistant Chronic myeloid leukemia Ph+ acute lymphoblastic leukemia |
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Sorafenib
Class MOA phamacokinetics |
intracellular signaling antagonist
multi-kinase inhibitor (kinases involved in proliferation and angiogenesis) Kinases: RAF, VEGFR-2/3, PDGFR-beta, KIT, FLT-3, RET (optional) Oral |
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Name 2 drugs that inhibit mTOR intracellularly.
Route of admin? Clinical use? (optional) |
Temsirolimus - IV infusion, renal cell carcinoma
Everolimus - oral, renal cell carcinoma mTOR - a serine/threonine protein kinase |
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Protezomib
class MOA |
Proteosome inhibitor
binds to the 20S core of the 26S proteosome and blocks the activity of proteosome proteosome - for non-lysosomal protein degradation; degrades misfolded proteins |
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Name 2 drugs that inhibit angiogenesis.
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Bevacizumab
sunitinib |
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Bevacizumab
Class MOA |
monoclonal antibody
angiogenesis inhibitor targets VEGF |
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Sunitinib
Class MOA route of admin |
Angiogenesis inhibitor
similar to Sorafenib inhibition of multiple kinases: PDGFR-alpha and PDGFR-beta, VEGFR1, VEGFR-2, VEGFR-3, c-kit (optional) |
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Vorinostat
Class MOA clinical use (optional) |
intracellular antagonist
Histone deacetylase inhibition --> hyperacetylation --> tumor cell arrest, differentiation, or apoptosis Cutaneous T cell leukemia (CTCL) |
