Central Neurotoxicity in Cancer Chemotherapy: Pharmacogenetic inSights

Abstract

Central neurotoxicity of chemotherapy is likely to be multifactorial. There are two hypotheses regarding endogenous mechanisms that may be involved, namely the target and the blood-brain barrier transporter hypotheses. Here, we will review candidate genetic determinants for the risk of chemotherapy-induced neurotoxicity, such as polymorphisms involved in the target mechanism. These include polymorphisms in folate metabolizing enzymes and apolipoprotein E, as well as those in blood-brain barrier transporter genes. Currently, the exact role of pharmacogenetics in mechanisms that lead to central neurotoxicity of chemotherapy has not been fully unraveled. Larger, prospective, longitudinal and more uniform studies are needed, with prechemotherapy and follow-up measurements of neuropsychological performance, MRI, PET, genetic profiles and biomarkers relevant for the proposed target and transporter mechanisms.

Central Nervous System Complications in Children Receiving Chemotherapy or Hematopoietic Stem Cell Transplantation

“…The non-synonymous C677T and A1298C variants in the 5,10-methylenetetrahydrofolate reductase are among the most widely studied. However, results are conflicting, main reasons being small and heterogeneous populations and differences in protocols and criteria defining toxicity (70, 71). Prevention of MTX neurotoxicity based on leucovorin rescue has been adopted in most protocols; however, its use is limited by rescue effect exerted even on leukemic cells and its efficacy in preventing neurotoxicity is partial (20).…”

Translational approaches to treatment-induced symptoms in cancer patients

“…(83, 84) Other candidate genetic determinants for increased sensitivity of the brain to inflammatory injury involve the E4 allele of the apolipoprotein gene that compromises neuronal repair and plasticity, and polymorphism in the catechol-O-methyl transferase enzyme that regulates the amount of dopamine in the frontal cortex. (85) These genetic polymorphisms are associated with a higher risk of cognitive dysfunction in response to chemotherapy in breast cancer and lymphoma patients. (86)…”

Chemotherapy-induced neurotoxicity in pediatric solid non-CNS tumor patients: An update on current state of research and recommended future directions

“…Several chemotherapeutic agents can cause central neurotoxicity [87] by crossing the BBB readily. Direct damage to the BBB was shown in animal studies for agents such as cisplatin [78] (see Table 2).…”

“…Given that disturbance of the folate metabolism may eventually result in demyelination, as well as in endothelial damage and in intensive stimulation of N-methyl-D-aspartate (NMDA) receptors in the brain [87], the association between these polymorphisms and neurotoxicity due to MTX has been extensively investigated [107,108].…”