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Medline ® Abstract for Reference 83

of 'Overview of neurologic complications of non-platinum cancer chemotherapy'

Regulatory polymorphisms inβ-tubulin IIa are associated with paclitaxel-induced peripheral neuropathy.
Leandro-García LJ, LeskeläS, Jara C, Gréen H, Avall-Lundqvist E, Wheeler HE, Dolan ME, Inglada-Perez L, Maliszewska A, de Cubas AA, Comino-Méndez I, Mancikova V, Cascón A, Robledo M, Rodríguez-Antona C
Clin Cancer Res. 2012;18(16):4441. Epub 2012 Jun 20.
PURPOSE: Peripheral neuropathy is the dose-limiting toxicity of paclitaxel, a chemotherapeutic drug widely used to treat several solid tumors such as breast, lung, and ovary. The cytotoxic effect of paclitaxel is mediated throughβ-tubulin binding in the cellular microtubules. In this study, we investigated the association between paclitaxel neurotoxicity risk and regulatory genetic variants inβ-tubulin genes.
EXPERIMENTAL DESIGN: We measured variation in gene expression of threeβ-tubulin isotypes (I, IVb, and IIa) in lymphocytes from 100 healthy volunteers, sequenced the promoter region to identify polymorphisms putatively influencing gene expression and assessed the transcription rate of the identified variants using luciferase assays. To determine whether the identified regulatory polymorphisms were associated with paclitaxel neurotoxicity, we genotyped them in 214 patients treated with paclitaxel. In addition, paclitaxel-induced cytotoxicity in lymphoblastoid cell lines was compared withβ-tubulin expression as measured by Affymetrix exon array.
RESULTS: We found a 63-fold variation inβ-tubulin IIa gene (TUBB2A) mRNA content and three polymorphisms located at -101, -112, and -157 in TUBB2A promoter correlated with increased mRNA levels. The -101 and -112 variants, in total linkage disequilibrium, conferred TUBB2A increased transcription rate. Furthermore, these variants protected from paclitaxel-induced peripheral neuropathy [HR, 0.62; 95% confidence interval (CI), 0.42-0.93; P = 0.021, multivariable analysis]. In addition, an inverse correlation between TUBB2A and paclitaxel-induced apoptosis (P = 0.001) in lymphoblastoid cell lines further supported that higher TUBB2A gene expression conferred lower paclitaxel sensitivity.
CONCLUSIONS: This is the first study showing that paclitaxel neuropathy risk is influenced by polymorphisms regulating the expression of aβ-tubulin gene.
Spanish National Cancer Research Center, Madrid, Spain.