In cancer chemotherapy of acute lymphocytic leukaemia, administration of drugs such as 6-mercaptopurine and 6-thioguanine can cause severe haematological toxicity or even death in patients possessing nonfunctional variants of thiopurine methyltransferase (TPMT). Genotyping of TPMT can identify those patients who are homozygous for alleles encoding nonfunctional enzyme, and therefore unable to metabolize the drugs to their inactive forms. These patients can be safely treated with doses 10 to 15 times less than commonly prescribed.
Human genetic variability can be expected to affect all treatment modalities. For example, breast cancer treatment with transtuzumab (Herceptin), a humanised monoclonal antibody against the HER2 receptor, is linked to HER2 overexpression which is a marker for responsiveness to transtuzumab therapy.
Warfarin is a widely used oral anticoagulant with a narrow therapeutic index and wide interindividual variation in dose requirement. A large number of pharmacogenetic studies have revealed that genetic polymorphisms in the genes encoding drug-metabolizing enzymes CYP2C9 and the warfarin target protein vitamin K epoxide reductase complex 1 (VKORC1) may affect the response to warfarin. Genetic tests are now available to guide the dosage of warfarin therapy. |