Central Neurotoxicity in Cancer Chemotherapy

Pharmacogenetic Insights

Femke EAM Froklage; Jaap C Reijneveld; Jan J Heimans

Disclosures

Pharmacogenomics. 2011;12(3):1-17. 

In This Article

Abstract and Introduction

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.

Introduction

Central neurotoxic side effects of chemotherapy are the main reason to limit the dose of chemotherapy in many patients, despite the protective role of the blood–brain barrier (BBB). Cancer patients may experience a wide range of neurological symptoms due to chemotherapy, such as cognitive deficits, seizures, cerebellar dysfunction, psychiatric symptoms and extrapyramidal disorders.[1,2] The development of these harmful effects may have an acute, subacute, or delayed course, and may be reversible or (partially) irreversible.[1,3,4] The incidence of central neurotoxicity of chemotherapy depends on the chemotherapeutic drug used, the frequency of administration, the dosage prescribed, the route of administration and concomitant cranial irradiation.[1,2,5–7] These are all well-known exogenous risk factors; however, little is known regarding differences in predisposition to developing central neurotoxicity. Although the cause of central neurotoxicity of chemotherapeutic treatment is likely to be multifactorial, two basic underlying endogenous mechanisms can be distinguished: vulnerability of the CNS to the pharmacological effects of antineoplastic drugs – the 'target hypothesis' and the insufficient functioning of drug transporters at the BBB resulting in inadequate protection of the CNS against the potentially toxic effects of chemotherapy – the 'transporter hypothesis'. Genetic profiles may play an important role in both mechanisms, and may furthermore determine an individual's susceptibility to experiencing neurotoxic side effects of chemotherapy.

In this article, we will provide an outline of the consequences and causes of central neurotoxicity of chemotherapy, with special attention paid to cognitive deficits, as these are the most widely studied functional neurological side effects of chemotherapy.[8] Also of particular interest is methotrexate (MTX)-induced central neurotoxicity, owing to its relatively high incidence, and the recent identification of suspected pharmacogenetic determinants of MTX-based CNS toxicity of chemotherapy.[1,9] Subsequently, we will discuss the role of target and transporter mechanisms in the development of central neurotoxicity, and focusing, in particular, on the genetics underlying these mechanisms.

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