The ABCB1 3435 T allele does not increase the risk of paclitaxel-induced neurotoxicity

Abstract

Paclitaxel is a frequently used anticancer drug with considerable inter-individual variability in terms of drug efficiency and toxicity. The reasons for this variability have not been fully explained. The purpose of this study was to evaluate the possible relationship between paclitaxel-induced neurotoxicity and the distribution of genetic variations with reported functional significance in the ABCB1, CYP2C8 and CYP3A4 genes that are all implicated in taxol metabolism. Women (n=36) experiencing paclitaxel-induced neurotoxicity were included in the study, and the ABCB1 G2677A/T and C3435T as well as CYP2C8(*)3 and CYP3A4(*)1b allele frequencies were determined using PCR-RFLP and DNA sequence analysis. We showed that the ABCB1 3435T allele, previously reported as a risk allele for neurotoxicity, did not correlate with the occurrence of neurotoxicity in our patient sample (Chi-square test, p=0.61). Furthermore, we showed that neither the CYP2C8(*)3 nor CYP3A4(*)1b alleles, that both lead to diminished enzyme activity, correlated with paclitaxel-induced neurotoxicity. The occurrence and variation in severity of neurotoxicity in our Swedish patient sample could therefore not be explained by the reported functional polymorphisms in the ABCB1, CYP2C8 and CYP3A4 genes.

Figure 1

Scatter dot plot showing the paclitaxel dose when the patient first experienced neurotoxicity grade 1. The individuals are grouped based on diagnosis. The patients, regardless of diagnosis, that had received previous chemotherapy are also shown. Information about dose is absent for one of the breast cancer patients.

Figure 2

Scatter dot plot showing the paclitaxel dose when the patients first experienced neurotoxicity grade 1 and/or grade 2. Patients are grouped according to the ABCB1 3435C/T alleles. Information about dose is absent for one of the breast cancer patients with the allele T/T.