Anti-cancer: alkylating agents Flashcards
Are alkylating agents cell-cycle specific or non-specific?
cell cycle non-specific (CCNS)
What is the general MoA of the alkyating agents?
they attach their alkyl groups to constituents on cells, particularly DNA, causing cell death
Specific MoA
the mechanism involves intramolecular cyclization to form an ethyleneimonium ion that may directly or through formation of a carbonium ion transfer an alkyl group to a cellular constituent
Where is the major site of alkylation within DNA?
N7 position of the guanine
What are the mechanisms of resistance to the polyfunctional alkylating agents?
decreased cell permeability to the drug, increased repair of DNA, increased levels of glutathione to deactivate the electrophilic alkylating agent (glutathione conjugates it), increased glutathione-S-transferase activity
What are the toxicities of the alkylating agents?
Nausea/vomiting, bone marrow depression, alopecia
How does alkylating lead to cell death?
covalent binding of the agents with the DNA leads to miscoding or excision (excision leads to strand breakage)
What kinds of cells are most susceptible to alkylation?
replicating cells
Cyclophosphamide is what type of agent?
bifunctioning
Cyclophosphamide is from what class?
Bis(chlorotheyl)amines
How is cyclophosphamide administered?
orally
What activates cyclophosphamide?
cytochrome P450 enzyme system in the liver - but the liver will continue to metabolize to inactivate some in order to protect itself
What is the activation step for cyclophosphamide?
P450 system breaks it down into active metabolites, then they are delivered to tumor and normal tissue. Then nonenzymatic cleavage of aldophosphamide converts it to cytotoxic forms
What are the cytotoxic forms?
phosphoramide mustard and acreolein
