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126 Cards in this Set
- Front
- Back
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Nitrogen mustard, alkyl sulfonates, nitrosoureas, triazenes-methylhydrazines and platinum complexes belong to what class of chemotx agents?
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Alkylating agents
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Chemotherapeutic effects of alkylating agents are directly related to what:
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Alkylation of DNA
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What is the chemical group responsible for nucleophilic attack with alkylating agents?
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Chlorethyl group - chloride is a good leaving group
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What part of DNA molecule is most susceptible to nucleophilic attack by alkylating agents?
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N7 of guanine
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Alkylation of N7 of guanine changes base pairing how?
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G:T now instead of G:C
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Cytotoxicity predominates in bifunctional or monofunctional alkylating agents?
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Bifunctional
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Bifunctional/monofunctional alkylating agents have greater capacity for mutagenesis and carcinogenesis?
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Monofunctional
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InterDNA strand cross linking occurs with bifunctional/monofunctional alkylating agents?
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Bifunctional
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When an alkylating agent is used as a single agent, what develops rapidly?
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Resistance to the alkylating agent
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What is the dose limiting toxicity with alkylating agents?
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Myelosuppression (BM toxicity)
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Mucosal toxicity, neural toxicity, alopecia, and sterility are also side effects of what chemotx?
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Alkylating agents
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Nitrogen mustards belong to what class of chemotx drugs?
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Alkylating agent
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What is the primary mechanism of action of nitrogen mustards?
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Formation of bi-functional crosslinks
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What drug is used in the treatment of lymphomas?
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Mechlorethamine (Nitrogen mustard)
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Mechlorethamine is what kind of drug?
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Nitrogen mustard
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Mustargen is what kind of drug?
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Nitrogen mustard
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Why can nitrogen mustards not be detected with in a few minutes of IV in plasma?
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Highly reactive in plasma solutions
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In vitro, peak DNA damage with nitrogen mustard occurs when?
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Within the first hour
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What is the primary site of alkylation with nitrogen mustard?
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N7 of guanine
N7 of adjacent guanine or adenine |
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What is the major toxicity of nitrogen mustard?
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Severe nausea and vomiting
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Cyclophosphamide is what kind of drug?
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Nitrogen mustard
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Name a stable nitrogen mustard
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Cyclophosphamide
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Is cyclophosphamide active as is?
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No, requires metabolic activation in liver to 4-OH cyclophosphamide
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What drug is associated with hemorrhagic cystitis?
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Cyclophosphamide
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What metabolite is responsible for hemorrhagic cystitis associated with Cyclophosphamide?
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Acrolein
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What sequestrant is given to bind acrolein and prevent hemorrhagic cystitis when giving Cyclophosphamide?
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Mesna
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What is the function of mesna
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Scavenge acrolein
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Name a toxic metabolite of cyclophosphamide:
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Acrolein
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Acrolein has an affinity for what type of cells?
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Bladder cells = hemorrhagic cystitis
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Melphalan is what kind of drug?
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Nitrogen mustard
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What drug is transported by the leucine transport uptake system?
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Melphalan
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What is the mechanism of action of melphalan?
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Similar to nitrogen mustard
Bifunctional alkylation of DNA |
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Nausea and vomiting is frequen/infrequent with melphalan?
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Infrequent
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Chlorambucil is what kind of drug?
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Nitrogen mustard
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Chlorambucil has a cyclohexyl ring structure that allows oral administration. The ring increases/decreases stability?
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Increases stability
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What is the mechanism of action of chlorambucil?
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Similar to nitrogen mustard
Bifunctional alkylation of DNA |
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What is the major toxicity (2) with chlorambucil?
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GI discomfort
Hepatoxicity |
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Busulfan belongs to what drug class?
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Alkyl sulfonates
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What is the mechanism of action of Busulfan?
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Crosslinking of DNA and proteins
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What is the major toxicity of busulfan?
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Myelosuppression
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Today busulfan use is replaced with what drug?
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Imatinib
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BCNU - Carmustine is what kind of drug?
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Chlorethylnitrosourea
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CENUs are highly lipophilic making them ideal for treatment of what kind of cancer?
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Brain tumors
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CCNU-Lomustine belongs to what class of drugs?
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Nitrosoureas
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Methyl-CCNU-semustine belongs to what class of drugs?
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Nitrosoureas
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CENU decomposes to form alkylating moiety to form chloroethylcarbonium ion. What is the action of this ion?
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Produce DNA intra and inter-strand crosslinks
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Name the two breakdown products of CENU (Chlorethylnitrosourea)
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1. chloroethylcarbonium ion
2. isocyanate |
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Isocyanate is a breakdown product of CENU. What is its function?
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Inactivate enzymes (reactive w/ lysine residue in proteins)
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What drugs cause severe delayed (4 weeks) myelosuppression?
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CENU
Carmustine, Lomustine, Semustine |
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What drug is specially useful for pancreatic islet cell CA?
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Methylnitrosourea-streptozotocin
(Antibiotic nitrosourea) |
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Where do antibiotic nitrosoureas act?
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Guanine O-6
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Do antibiotic nitrosoureas require metabolic activation?
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No they do not
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Antibiotic nitrosoureas are bifunctional or monofunctional?
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Monofunctional --> mutagenic and may be carcinogenic
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Name 2 triazene-methylhydrazines
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Dacarbazine (DTIC)
Procarbazne |
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MTIC kills cells in what phase of the cell cycle?
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All phases of the cell cycle
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DTIC must be metabolized in the liver and forms what metabolite?
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MTIC
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What is site of methylation with MTIC?
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O6-guanine
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What is the mechanism of action of procarbazine?
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DNA methylation that produces DNA strand breaks
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What drug is used in the treatment of Hodgkin's and brain tumors?
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Procarbazine
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Name two drugs used for brain tumors?
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Procarbazine and Carmustine (CENU Nitrosoureas)
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Is procarbazine bi or monofunctional?
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Monofunctional
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Platinum coordination complexes do/do not alkylate?
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Don't alkylate
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Platinum coordination complexes don't alkylate but do/do not form DNA cross links?
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Do form DNA cross links
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Cisplatin, carboplatin, and oxaliplatin are all what kind of drugs?
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Platinum coordination complexes
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What platinum derivative was approved for colon cancer?
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Oxaliplatin
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Platinum compounds themselves are/are not DNA reactive?
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Are not DNA reactive
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What must occur with platinum compounds in order to react with DNA?
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Undergo sequential aquation
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What do platinum compounds need?
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H2O
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What kind of adducts account for >95% of total platination site?
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Intrastrand adducts
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Carboplatin does/does not show cross-resistance with cisplatin?
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Does have cross resistance
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Oxaliplatin does/does not show cross resistance with cisplatin?
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Does not show cross resistance
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What is the major toxicity associated with platinum compounds?
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Ototoxicity
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What is the major toxicity of oxaliplatin?
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Peripheral neuropathy
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Name a SERM
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Tamoxifen
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What is the mechanism of action of Tamoxifen?
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Competitive inhibitor of estradiol binding to ER
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Tamoxifen binds to what receptor?
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Estrogen receptor
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What drug is used to treat women with ER+ metastatic breast cancer?
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Tamoxifen
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What kind of symptoms are common with tamoxifen use?
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Menopausal: hot flashes, vaginal atrophy
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What kind of cancer risk is increased with use of Tamoxifen?
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Endometrial CA
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What breast cancer drug increases the risk of thromoembolic events?
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Tamoxifen
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Name a SERD
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Fulvestrant
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What drug is second line for tamoxifen refractory patients?
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Fulvestrant
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What is a SERD
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Selective estrogen receptor downregulators
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What breast cancer drug is used in post menopausal women with ER+?
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Fulvestrant
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What steroidal antiestrogen inhibits dimerization and increases degradation of the estrogen receptor?
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Fulvestrant
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Name an aromatase inhibitor:
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Anastrazole
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Name two gonadotropin-releasing hormone agonists:
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Leuprolide
Goserelin |
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GnRH agonists cause surge in what hormones?
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LH and FSH
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What drug can be given with GnRH agonists to prevent the LH and FSH surge?
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Flutamide
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What drugs produce medical castration?
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Leuprolide
Gosrelin GnRH agonists |
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Name an androgen receptor blocker:
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Flutamide
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What is the mechanism of action of Flutamide?
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Androgen receptor blocker - inhibits ligand binding and AR nuclear translocation
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Name two immunostimulants:
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IFN-alpha 2a
IFN - alpha 2b |
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What drugs are approved for malignant melanoma?
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IFN-alpha
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What drug is approved for hairy cell leukemia?
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IFN-alpha
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Name a differentiating agent:
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ATRA (all trans retinoic acid)
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What drug is used to treat promyelocytic leukemia (AML-M3)
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ATRA
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What leukemia has fusion of the retinoic acid receptor gene to the promyelocytic leukemia (PML) gene?
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AML-M3
Acute Promyelocytic Leukemia |
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Name a tyrosine kinase inhibitor used for CML?
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Imatinib (Gleevec)
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What is imatinib used to treat?
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CML t(9;22) Bcr-abl fusion
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Bcr-abl fusion has what effect on the tyrosine kinase?
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Constitutively active
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Name two other tyrosine kinase inhibitors besides imatinib:
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1. Geftinib
2. Erlotinib |
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What is the mechanism of action of Geftinib?
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EGFR tyrosine kinase inhibitor
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What is the mechanism of actin of Erlotinib?
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EGFR tyrosine kinase inhibitor
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What agent is approved for non-small cell lung CA that has failed standard chemo?
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Geftinib
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What agent is approved for locally advanced or metastatic non-small cell lung CA?
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Erlotinib
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What humanized mAB is directed against Her2/Neu?
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Herceptin (Trastuzumab)
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Her2/Neu is overexpressed in how many % of breast tumors?
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30%
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What drug is approved for first-line therapy against metastatic Her2+ CA?
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Herceptin (trastuzumab)
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What is the main toxicity with Herceptin?
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Cardiotoxicity
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Herceptin in combination with doxirubicin has what potential toxic effect?
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Cardiotoxicity
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What drug prevents VEGF from binding to VEGF-R?
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Bevacizumab (Avastin)
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What mAB is a competitive antagonist at EGFR?
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Cetuximab
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Name a CD20 directed antibody:
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Rituximab
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What mAB binds to the surface of B cells at CD20 and triggers an immune attack?
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Rituximab
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What is the antitumor property with glucocorticoids?
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Activate GR and initiate apoptosis
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What agent is used in combo therapy for ALL in children?
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Glucocorticoids
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Dexamethasone and prednisolone are what kind of agents?
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Glucocorticoids
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What kind of drug is vorinostat?
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HDAC inhibitor
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What drug modulates epigenetic activities by inhibiting Histone deacetylase?
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Vorinostat
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What drug is approved for Cutaneous T cell lymphoma?
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Vorinostat
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What drug is a SAHA?
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Vorinostat
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What drug is a proteosomal inhibitor?
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Bortezomib
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What drug prevents degradation of proapoptotic factors?
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Bortezomib
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What drug is approved to treat relapsed multiple myeloma?
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Bortezomib
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What drug is approved to treat mantle cell lymphoma?
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Bortezomib
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