alkylating agents and Platinum compounds Flashcards
What does bifunctionality mean for alkylating agents?
2 alkylating groups that produces DNA intra- and interstrand linkages; most effective anti-cancer drugs
How does alkylating agents work?
potent electrophiles that react with nucleophillic groups and results in an alkyl group transferring onto DNA/protein
What are the alkyl agents derived from?
Mechlorethamine
What does Mesna do with Cyclophosphamide?
blocks hemorrhagic cystitis; is a charged compound that netralized acrolyin in bladder
What is the difference between Platinum compound crosslinking and Alkylating agents?
Platinum compounds- covalent intrastrand crosslinkers on cis groups; causes geometry contraints on DNA (sharp bend, pucker)
Alkylating agents- intra- and interstrand crosslinking; bifunctional agents and have 2 alkylating groups
What are the alkylating agents?
Mitomycin C, Cyclophosphamide, Chlorambucil
-mitomycin C has myelosuppression as dose-limiting
What is cisplatin?
-platinum compound
-aquo form is reactive (potent electrophile) and causes restraints on DNA/sharp bend in DNA
-dose-limiting nephrotoxicty
What drugs require activation via an enzymatic process?
cyclophosphamide requires hydroxylation by cytochrome P450
-not required for platinum based therapies
What are the mechanisms of resistance to alkylating agents and platinum based compounds?
-increased intracellular concentration of glutathione (high reactivity); will react with intermediates of alkylating agents
-increased expression of glutathione S-transferase
What part of the cell cycle do alkylating agents target?
-non cell cycle specific
-more susceptible to G1/S phases
What is chlorambucil
-mechlorthamine derivative
-able to be used in patients because of decreased nucleophilicity of nitrogen by adding aryl groups
