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Multiple molecular mechanisms underlying cellular resistance to cisplatin. Cisplatin uptake into cells can be limited by mutations in the uptake transporter
CTR1 (SLC31A1) resulting in drug resistance (A). Once inside the cell, one of the 2 Cl groups is replaced by water producing a reactive nucleophilic
species that enters the nucleus where it can covalently modify DNA (primarily by intrastrand binding to adjacent guanines) and cause cell death.
Resistance can occur when the damaged DNA is repaired (eg, nucleotide excision repair) or the damaged DNA is "tolerated" (eg, loss of mismatch repair
or downregulation of apoptotic pathways) (B). Prior to entering the nucleus, conjugation of the activated cisplatin with glutathione (GSH) by GSH Stransferases (GSTs) (C), or interaction with the sulfhydryl-containing metallothioneins (D) can result in reduced drug efficacy. Finally, resistance can occur
Source: Drug Resistance, The Basic Science of Oncology, 5e
if intracellular levels of cisplatin or its metabolites are reduced by the efflux activity of several membrane transporters, including the MRP2 (ABCC2) efflux
IF, Hill RP,
Bristow RG, Harrington
L. The Basic
Science of Oncology, 5e; 2016 Available at: http://mhmedical.com/
pump and theCitation:
ATP7B Tannock
P-type adenosine
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(E).
Accessed: June 10, 2017
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