Some tumors are resistant to chemotherapy with alkylating agents. The resistance can arise from a number of mechanisms.
Resistance mechanisms can be divided into those that limit the formation of cytotoxic DNA lesions (“pre-target”) or that allow a tumor cell to repair or tolerate the damage (“post-target”).
Mechanism
Explanation
decreased drug accumulation (concentration) within tumor cells
failure of drug to enter cell; transport of drug out of cell
decreased activation
failure to metabolize a drug that needs to be activated into its active state
increased deactivation or detoxification
increased protein binding of cytotoxic drugs
metallothioneins are proteins with a high cysteine content that bind to alkylating agents
increased repair of DNA damage
MGMT, APNG, NER pathway, etc
post-replicative repair
ability of a cell to synthesize DNA past the site of DNA damage
defective mismatch repair
increased mutation rate
development of clones resistant to the alkylating agent
failure of apoptotic mechanism
inhibition of programmed cell death by bcl2; mutations in p53 causing impaired induction of apoptosis following DNA damage
Identifying a tumor that is resistant before starting therapy would seem a whole lot smarter rather than waiting until afterwards.
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