Pharmacogenetics of Childhood Acute Lymphoblastic Leukemia

Elixabet Lopez-Lopez; Angela Gutierrez-Camino; Nerea Bilbao-Aldaiturriaga; Maria Pombar-Gomez; Idoia Martin-Guerrero; Africa Garcia-Orad

Disclosures

Pharmacogenomics. 2014;15(10):1383-1398. 

In This Article

Pharmacogenetics of Vincristine

Vincristine is an antimitotic agent that acts by inhibiting microtubule assembly through binding to tubulin. Despite its extended use in different phases of treatment, vincristine can cause hematologic toxicity and dose-dependent neurotoxicity, its most important adverse effect.[115]

To date, there have been few studies that have analyzed the association between genetic polymorphisms and vincristine toxicity in childhood ALL. Four studies have studied polymorphisms in CYP3A5,[116–119] responsible for metabolic clearance of vincristine in ALL patients. Two of them found association between CYP3A5*3, *6 and *7 polymorphisms and vincristine-induced neuropathy.[116,117] However, the other two studies did not find any association.[118,119] One study analyzed MAPT and ABCref-1, a transporter involved in vincristine elimination from the cells, and another study analyzed ABCref-1 only. These studies included a total of six SNPs in MAPT (A68504G, A80659G, C90092T, T96360C, T96214C and T102787C) and three in ABCref-1 (C3435T, C1236T and G2677A/T), without finding any association with toxicity.[119,120]

The limited number of performed studies and the conflicting results have failed to define toxicity markers for vincristine. This could be due in part to the relatively small sample sizes, without sufficient power to detect small effects, and also to the fact that these studies are based on few candidate genes and few SNPs within each gene, and/or to differences in treatment guidelines. So it is difficult to draw firm conclusions.

On the other hand, some authors have shown interest in the role of miRNA expression in vincristine resistance. In a recent study, leukemic cells were collected from 61 patients with B-cell ALL and in vitro resistance to vincristine was analyzed. When they compared the miRNA expression profile at diagnosis of the patients whose leukemic cells were resistant to vincristine versus those that were sensitive, ten miRNAs out of 397 analyzed were differentially expressed. The most remarkable result was the 14- to 25-fold upregulation of miR-125b, miR99a and miR-100 in resistant patients.[121] In a subsequent study, coexpression of two or three of those miRNAs in Reh cells was shown to increase in vitro resistance to vincristine.[122] These data suggest that changes in miRNA expression or function could have an effect on vincristine response.

In brief, studies with a sufficient set of patients following standard treatment and with a larger number of genes and polymorphisms are needed to find good markers of vincristine-induced neurotoxicity. Further miRNA studies may also reveal interesting markers.

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