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69 Cards in this Set

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