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The aim of the present work was to assess whether polymorphisms in genes coding for drug transport proteins may influence dosing, efficacy and toxicity of maintenance therapy with methotrexate (MTX) and 6-mercaptopurine (6MP) in childhood acute lymphoblastic leukemia (ALL). A total of 41 children with ALL were screened for 10 SNPs in the SLC19A1, ABCB1, ABCC2, ABCC4 and ABCG2 transporter genes by means of direct sequencing. Carriers of the ABCC4 934CC and ABCB1 1236TT genotypes received a lower percentage of the protocol-recommended starting dose of MTX (62.1 vs. 81.3% for 934CA carriers, p=0.001) and 6MP (73.1 vs. 87.7% for 1236CC/CT carriers; p=0.026), respectively. The C1236T SNP also increased the efficiency of myelosuppression. Median (and interquartile) number of blood tests with leukocytes levels <310(9)/L for the CC; CT and TT genotypes were 22 (13), 30.5 (11.75) and 33 (17.25), respectively (p=0.001). In addition, this SNP also correlated with the number of hematological adverse events (p=0.004 for the difference between same genotypes). The event more profoundly affected was neutropenia (p=0.004). In the same manner, the ABCC4 934CC genotype was also associated to more frequent hematological toxicity (p=0.041 vs. CT carriers) and raised LDH levels (p=0.004 vs. CT carriers); although only the latter association remained significant after correction by multiple testing. Overall, our findings indicate that variability in the ABCB1 and ABCC4 genes may confer higher sensitivity to maintenance chemotherapy of ALL, and therefore its determination may be helpful in individualizing this treatment.
This article was published in the following journal.
Pediatric acute lymphoblastic leukemia (ALL) affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in three stages, with the longest ph...
We have aimed to determine the effect of polymorphisms in regulatory regions of the DHFR gene in relation to methotrexate (MTX) dose adjustments and drug-induced toxicity in children on maintenance th...
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The current study is part of a large multi-investigator grant to look at the pharmacogenetics of a number of membrane transporters. Previously, the investigators have recruited a cohort o...
The current study is part of a large multi-investigator grant to look at the pharmacogenetics of a number of membrane transporters. Previously, we have recruited a cohort of healthy volun...
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Genes that have a suppressor allele or suppressor mutation (SUPPRESSION, GENETIC) which cancels the effect of a previous mutation, enabling the wild-type phenotype to be maintained or partially restored. For example, amber suppressors cancel the effect of an AMBER NONSENSE MUTATION.
A high-affinity, low capacity system y+ amino acid transporter with strong similarity to CATIONIC AMINO ACID TRANSPORTER 1. The two isoforms of the protein, CAT-2A and CAT-2B, exist due to alternative mRNA splicing. The transporter has specificity for the transport of ARGININE; LYSINE; and ORNITHINE.
The effect of herbs, other PLANTS, or PLANT EXTRACTS on the activity, metabolism, or toxicity of drugs.
The study of the relationship between NUTRITIONAL PHYSIOLOGY and genetic makeup. It includes the effect of different food components on GENE EXPRESSION and how variations in GENES effect responses to food components.
An effect usually, but not necessarily, beneficial that is attributable to an expectation that the regimen will have an effect, i.e., the effect is due to the power of suggestion.
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