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69 Cards in this Set
- Front
- Back
Alkylating agents: Nitrogen Mustards
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cyclophosphamide, ifosfamide, chlorambucil, mechlorethamine,
melphalan, bendamustine |
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The ________ of guanine is particularly susceptible to the formation of a covalent bond with bifunctional alkylating agents and may well represent the key target that determines their biological effects
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7 nitrogen atom
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The alkylating agents used in chemotherapy share the capacity to contribute ________ to biologically vital macromolecules such as DNA
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alkyl groups
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alkyl sulfonate?
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Busulfan
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Triazine alkylating agent?
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dacarbazine
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The active moiety of alkylating agents is?
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chloroethylamine
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The biological activity of nitrogen mustards is based upon the presence of the ____________________?
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bis -(2-chloroethyl) grouping
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The most widely used alkylating agent?
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cyclophosphamide
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monofunctional methylating agents (_______, _______), have greater capacity for mutagenesis and carcinogenesis
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procarbazine, temozolomide
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Platinum coordination complexes?
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cisplatin, carboplatin, oxaliplatin
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The Mechanism of Action of Alkylating Agents involves metabolic activation to form __________or related transition complexes, which are strong electrophiles.
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carbonium ion intermediates
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Alkylating agents covalently bind DNA, causing _____or______
cross-linkage of DNA |
interstrand or intrastrand
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DNA adducts inhibit DNA replication and transcription leading to?
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breaks and miscoding
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Alkylating agents are not cell specific and should be avoided in ___________.
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Pregnancy
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Other DNA base targets of alkylating agents include?
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-N1 and N3 of adenine
-N3 of cytosine -O6 of guanine |
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CYTOXAN, NEOSAR?
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Cyclophosphamide
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Cyclophosphamide dosing:
100 mg/m2, PO daily for 2 weeks or 500 mg/m2, IV every 2-4 weeks. Used to treat ________________? |
lymphoma, breast cancer, acute lymphocytic leukemia (ALL ) and ovarian cancer
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Cyclophosphamide is metabolized by?
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CYP2B
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Cyclophosphamide and renal impairment?
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negligible fe, NO dose adjustment for renal impairment
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Cyclophosphamide toxicities?
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• Myelosuppression
• GI ulceration • Hemorrhagic cystitis (counteracted by mesna (sulfonate) and diuresis • Cardiotoxicity at high doses • Hepatic toxicity at high doses |
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True or false?
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Cyclophosphamide is a prodrug that must be metabolized to active metabolites in the liver.
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Cyclophosphamide metabolite responsible for anti-tumor effects?
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Phosphoramide mustard
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Cyclophosphamide metabolite responsible for hemorrhagic cystitis?
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Acrolein
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Ifex?
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Ifosfamide
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Ifosfamide is activated by CYP3A4 more slowly than cyclophosphamide and with greater production of dechlorinated metabolites and hloroacetaldehyde. These differences in metabolism likely account for the _______ doses of ifosfamide required for equitoxic effects.
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higher doses
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Ifosfamide is given 1.2 g/m2/day,IV for 5 days every 3-4 weeks and ised used for ______and ______cancer.
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lymphoma and breast
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Clinical toxicities of Ifosfamide include?
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• severe CNS toxicity
• myelosuppression • hemorrhagic cystitis, alleviated by mesna and diuresis • GI toxicity (nausea, vomiting) |
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The active metabolite of Ifosfamide is?
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Phosphoramide mustard
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Ifosfamide also produces?
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Acrolein
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Chlorambucil uses?
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-chronic lymphocytic leukemia (CLL)
-Hodgkin's lymphoma -non-Hodgkin's lymphoma (NHL) |
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Chlorambucil doses and metabolism?
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0.1 - 0.2 mg/kg PO daily for 3-6 weeks. Hepatic metabolsim
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Chlorambucil toxicities?
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myelosuppression
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Mechlorethamine HCl (MUSTARGEN®) uses?
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Hodgkin's disease; non-Hodgkin's lymphoma
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Mechlorethamine HCl (MUSTARGEN®) doses?
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6 mg/m2 IV on days 1 and 8 every 4 weeks
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Mechlorethamine HCl (MUSTARGEN®) toxicities?
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-GI
-Strong vesicant (extravasation into surrounding tissue causes sever damage. Sodium thiosulfate should be available for treatment) |
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Melphalan treatment?
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multiple myeloma
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Mephalon dosing?
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6 -8 mg PO for 4 days every 4 weeks or 15 mg/m2 IV once every 2-4 weeks. cancer type: multiple myeloma (MM).
- clinical toxicities • myelosuppression - pharmacokinetics • incomplete and variable oral absorption • t1/2 ≈ 45-90 min • fe ≈ 0.1-0.3, dose reduction for renal impairment |
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Mephalon PK?
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pharmacokinetics
• incomplete and variable oral absorption • t1/2 ≈ 45-90 min • fe ≈ 0.1-0.3, dose reduction for renal impairment |
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Mephalon toxicities?
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myelosuppression
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Bendamustine uses?
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Treatment of chronic lymphocytic leukemia (CLL)
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Active moiety of Bendamustine?
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Two terminal Cl molecules off of the nitrogen end.
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Cancer types treated with Bendamustine?
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Lymphoma and chronic lymphocytic leukemia (CLL)
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clinical toxicities of Bendamustine?
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Myelosuppression and GI toxicity
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Esters of alkanesulfonic acids alkylate DNA through the release of?
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methyl radicals
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An ester drug of alkanesulfonic acid is?
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Bisulfan
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Bisulfan is used to treat?
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Chronic myelogenous leukemia (CML)
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Bisulfan doses?
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2-8 mg PO daily for 3-6 weeks
1 mg/kg IV every 6 hours for 4 days |
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Bisulfan toxicities?
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• myelosuppression
• hepatotoxicity at high dose • CNS toxicity at high dose • GI toxicity at high dose |
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Bisulfan metabolism?
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extensive hepatic
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Dacarbazine uses?
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Lymphoma, melanoma
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Dacarbazine doses?
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3.5 mg/kg IV daily for 10 days, every 4 weeks
250 mg/m2 IV daily for 5 days, every 3 weeks |
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Dacarbazine toxicities?
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• myelosuppression
• GI toxicity (nausea, vomiting) • hepatotoxicity (when used in combination) |
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Procarbazine uses?
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Lymphoma
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Oral only antineoplastic agent?
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Procarbazine
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Clinical toxicities or procarbazine?
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• myelosuppression
• GI toxicity (nausea, vomiting) |
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True or false, platinum coordination complexes are alkylating agents?
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False
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Mechanism of Action of Platinum Complexes involves activation by?
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Low intracellular Cl concentration
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Platinum complexes react with DNA forming _______(favored) and
interstrand cross-links, with ___of___ as the primary target. |
N7 of Guanine
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Platinum complexes are not cell cycle specific, however, they are most effective in the __ Phase.
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S phase
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Cisplatin is used to treat?
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Lung and breast cancer and melonoma
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no ____needles or equipment can be used in preparing or
administering tcisplatin. |
Aluminum
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Cisplatin pharmacokinetics?
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• t1/2 > 24 hours
• rapid distribution to kidney, liver, intestine and testes • mainly urinary excretion, minimal biliary or intestinal excretion |
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Cisplatin toxicities?
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• nephrotoxicity (alleviated by chloride diuresis and amifostine-ETHYOL®)
•vomiting and nausea, alleviated by aripetant-EMEND®) • myelosuppression (mild to moderate) • increased risk of AML following chronic treatment |
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Carboplatin is used to treat?
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Lung, lymphoma and ovarian cancer
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Carboplatin requires dose adjustment for?
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renal impairment
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Carboplatin toxicities?
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-GI
lest than cisplatin |
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Oxaliplatin uses?
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colorectal and gastric cancers
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Major warning with Oxaliplatin?
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DO NOT use any chloride containing solutions to reconstitute
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Oxaliplatin toxicities?
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-peripheral neuropathy
-myelosuppression -GI toxicity |