An overview of the relations between polymorphisms in drug metabolising enzymes and drug transporters and survival after cancer drug treatment.
A wide interindividual variability in survival after cancer treatment is observed. This is attributable to many factors, including tumour and patient related factors. Genetic polymorphisms in drug metabolising enzymes and drug transporters may be one of these factors. Drug metabolising enzymes are responsible for the activation, inactivation and detoxification of many chemotherapeutic agents. Deficiencies in these enzymes may result in altered exposure (both extracellular and intracellular) to the chemotherapeutic agents, thereby influencing the efficacy of treatment. Drug transporters are important in the uptake and excretion of chemotherapeutic agents. Polymorphisms in drug transporter genes may influence the bioavailability and disposition of these agents. Studies have shown that variability in survival can (partly) be explained by polymorphisms in genes encoding drug metabolising enzymes and drug transporters. This review will discuss the role of genetic polymorphisms in drug metabolising enzymes and drug transporters in relation to survival after cancer treatment. The most important polymorphisms shown to influence survival after cancer treatment are polymorphisms in the genes encoding the phase II detoxification enzymes glutathione-S-transferases (GSTs). It appears that GSTM1 null and GSTT1 null have a clear association with longer overall survival in patients with different malignancies who are treated with substrates for these GSTs (mostly alkylating agents and platinum compounds). Genetic polymorphisms in GSTP1 and GSTA1 are also associated with an increased overall survival in patients with different malignancies. Most of the current data on the relation between treatment response and pharmacogenetics is derived from retrospective and exploratory studies. Prospective studies will be necessary.
Ekhart
Corine
C
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, The Netherlands. Corine.Ekhart@slz.nl
Rodenhuis
Sjoerd
S
Smits
Paul H M
PH
Beijnen
Jos H
JH
Huitema
Alwin D R
AD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics*; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic / Q000235:genetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D026901:Membrane Transport Proteins; D006899:Mixed Function Oxygenases; D005982:Glutathione Transferase