Chemotherapy Toxicity (Overview)
Dipl.-Biol. Birgit Busse
Many of the chemotherapeutics used in oncology may cause serious, potentially life-threatening side-effects. Genetically caused enzyme deficiencies can lead to a prolonged breakdown of the active agent which results in accumulation of the agent in the body and eventually to intoxication. A pharmacogenetic analysis before or during a chemotherapy provides the opportunity for individual adaption of the dosage while preventing risks of toxicity.
CYP2C8: The enzyme CYP2C8 is involved in the metabolism of paclitaxel. The CYP2C8*3 allele is associated with a reduced enzyme activity. In carriers of this allele, toxicity may arise due to the decreased metabolism of the drug.
CYP2D6: The enzyme CYP2D6 is involved in the prodrug activation of tamoxifen. Different variants in the CYP2D6 gene result in the loss or in the reduction of enzyme activity. Various studies with postmenopausal patients demonstrate that under treatment with tamoxifen the recurrence risk shows an association to the CYP2D6 genotype. Female patients with a functionally impaired CYP2D6 allele seem to be at a greater risk of recurrence than patients with two functional CYP2D6 alleles.
DPD: The enzyme dihydropyrimidine dehydrogenase plays a major role in the degradation of 5-fluorouracil (5-FU) and its prodrugs. Different variants in the DPD gene lead to formation of an enzyme with reduced or lacking acitivity; as a consequence the metabolism of DPD substrates is limited. Patients with DPD mutations are at a higher risk of developing severe toxicities under treatment with 5-FU.
TPMT: Thiopurine methyltransferase (TPMT) metabolizes thiopurines (e.g. azathioprine (AZA), 6-mercaptopurine (6-MP), 6-thioguanine (6-TG)) and represents a crucial factor in the inactivation of cytotoxic compounds. Variants in the TPMT gene are associated with TPMT deficiency, which may result in a fatal myelosuppression. The FDA has included the association between enzyme activity, genotype and dosage into the warnings/precautions section of the prescribing information.
UGT1A1: The enzyme UDP glucuronyltransferase (UGT1A1) is crucial in the degradation of irinotecan (topoisomerase I-Inhibitor). A dinucleotide expansion in the promoter region of the UGT1A1 gene leads to an enzyme deficiency, which results in accumulation of the toxic compound SN38 in the organism and thus in severe side-effects. The FDA has included the association between enzyme activity, genotype and dosage into the warning section of the prescribing information.