Mechanisms of anti-cancer drugs Flashcards
What type of drug is methotrexate?
Antimetabolite
What type of drug is 5-fluoracil
Antimetabolite
What type of drugs are BCNU, CCNU and methyl-CCNU?
Chloroethylnitrosureas which are alkylating agents
What type of drugs are chlorambucil, melphalan, mechlorethamine ?
Nitrogen mustards which are alkylating agents
What are the three modes of drug induced damage to DNA?
1) Covalent binding
2) Intercalation
3) Strand breakage
How can bleomycin be described
A radiomimetic drug
How do the majority of alkylating agents get taken up into cells
Non-specifically and passively
How is mechloroethamine taken up into cells
Due to its chemical similarity to choline it uses a choline transporter
How do cancers become resistant to mechloroethamine treatment?
Mutations in the choline transporter required for its uptake into cells
How is melphalan taken up into cells
Due to its chemical similarity to leucine/ other neutral amino acids; it’s actively transported into cells.
How do nitrogen mustards produce interstrand crosslinks on DNA
1) Random loss of a chlorine ion forms a positively charged intermediate which binds to the N7 on guanine. Same happens on the second arm of the nitrogen mustard which forms a bond with another N7 guanine on the other DNA strand creating an interstrand crosslink between the two strands.
Why does the major product of nitrogen mustards not produce a DNA interstrand crosslink?
Because both arms of the nitrogen mustard don’t react with DNA. One might react with an OH group instead which would produce a monofunctional, non-toxic adduct.
Why are chloroethylnitrosureas effective in mouse models compared to human cancers?
When chloroethylnitrosureas are metabolised they produce chloroethyl, a positively charged monoadduct which can adduct to N3 adenine, N7 guanine or O6 guanine. If it binds to O6 guanine then it goes on to form an interstrand crosslink. In mice, O6 methyltransferase is incapable of repairing the chloroethyl monoadduct as it is a highly specific enzyme. In humans it acts as a broader alkyltransferase so is able to repair chloroethyl guanine monoadducts before a crosslink is made. Therefore, it is not cytotoxic to cancer cells.
Why is treatment with BCNU, CCNU and methylCCNU effective in around one third of gliomas?
In these cancers, there is a loss of O6-methyltransferase expression. Therefore, the chloroethyl O6 guanine monoadduct is not repaired and goes on to produce an interstrand crosslink, becoming cytotoxic to the cell.
How do platinum drugs induce a cytotoxic effect in cancer cells
Have bifunctional Chlorine arms which form reactive intermediates. These react with OH and form a co-ordination complex that ultimately is able to produce mono/bifunctional adducts which are cytotoxic to the cancer cell.
