What is the mechanism of action in alkylating agents?
- produce strong electrophiles through carbonium or ethyleneimonium ion intermediates
- these covalently bind via alkylation of nucleophilic moieties in DNA
What is the most common site of alkylation?
N7 Position of guanine
Are alkylating agents cell cycle specific or nonspecific?
nonspecific
What are some side effects of alkylating agents?
- BM supression
- mucosal toxicity
- nausea and vomiting
- toxic effects on repro systems
- inc leukemic risk
How does resistance develop to alkylating agents?
- decreased permeability or uptake
- inc rates of catabolism
- inc DNA repair
- inc glutathione production
How does glutathione act on alkylating agents?
inactivates via conjugation
Name 3 types of nitrogen mustards?
- mechlorethamine - mustargen
- cyclophosphamide - cyclotoxan
- ifofasmide -Ifex
Where is mechlorethamine converted to an active metabolite?
body fluids or enzymatically converted in the liver
What is mechlorethamine used for?
- Hodkins disease
- topically for treatment of cutaneous T cell lymphoma
Why isnt mechlorethamine used much anymore?
it causes sterility
Where is cyclophosphamide and ifosfamide converted to an active metabolite?
in the liver by: hepatic cyt P450
-converted to phosphoramide mustard
What is cyclophosphamide used to treat?
- ALL
- CLL
- non hodkins lymphoma
- breast cancer
- lung cancer
- ovarian cancer
How are hemorrhagic cysts in the bladder prevented when a patient receives cyclophosphamide or ifosfamide?
adequate hydration and treatment with MESNA
By what method is cyclophosphamide and ifosfamide administered?
orally - relatively long half life 7-15 hours
What is ifosfamide used to treat?
- sarcoma
- testicular cancer
Which drugs have the side effect of hemorrhagic cysts in the bladder? Why does this occur?
cyclophosphamide and ifosfamide
What are two drugs of the nitrosureas category of alkylating agents?
- carmustine and Lomustine
What are carmustine and lomustine used to treat?
brain tumors - crosses the BBB
What are some serious side effects of nitrosureas ?
- renal toxicity
- pulmonary fibrosis
- profound myelosuppression
- severe nausea and vomiting
What are the three drugs that belong to the category of alkylating agents: triazenes?
- dacarbazine
- procarbazine
- temozolamide
Where is dacarbazine activated?
prodrug activated by liver cytochromes
What is the method of action of procarbazine?
forms free fradicals
What is the method of activation of temozolomide?
nonenzymatic conversion to methylhydrazine at physio pH
What is dacarbazine used to treat?
part of ABVD for hodkins disease
-also used for malignant melanoma
