Biochemistry - Membrane Structure

MDR1 gene polymorphisms affect therapy outcome in acute myeloid leukemia patients.

Illmer, T et al., 2002. Cancer Res. 62(17):4955-4962.

Allelic variants of the MDR-1 gene have been shown recently to influence protein expression and P-glycoprotein (P-gp) function in healthy volunteers. Therefore, 405 acute myeloid leukemia patients were investigated for somatic genotypes of the three most frequent single nucleotide polymorphisms (SNPs) in exons 12, 21, and 26. In all three loci, homozygous wild-type alleles were classified as genotype A, heterozygous as B, and homozygous mutant (alternative) allele as C. Patients with the C genotype in exons 12 and 26 showed a lower median age (both P < 0.05). Additionally, the C genotype in exons 12 and 26 was associated with cytogenetic poor risk aberrations (both P < 0.05). A possible regulatory impact of the SNPs on MDR1 mRNA expression was investigated by a Real time-PCR assay. MDR1 expression was strongly correlated with a decreased complete remission rate (P = 0.01) but failed to predict decreased overall survival (OS). There was a significant association of the A genotype in exons 21 (P = 0.05) and 26 (P < 0.05) with lower MDR1 expression, whereas the B variants showed highest MDR1 values at all three investigated gene loci. The A genotype in exon 26 was associated with lower OS (P < 0,01). In these patients, worse OS is likely attributable to an increased risk of relapse (P < 0.001). We were able to detect a linkage disequilibrium of the investigated SNPs, indicating combined polymorphisms that could affect the regulation of MDR1 expression. The A genotype of all SNPs demonstrated both lowest MDR1 values and significantly decreased OS (P < 0.05) with a high probability of relapses (P < 0.01). These observations indicate that allelic variants of the MDR1 gene may influence therapy outcome by additional mechanisms, different from P-gp expression on acute myeloid leukemia blasts, possibly involving pharmacokinetic effects of P-gp

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Bench meets bedside: A 10-year-old girl and amino acid residue glycine 75 of the facilitative glucose transporter GLUT1.

Klepper, J et al., 2005. Biochemistry 44(38):12621-12626.

Abstract

In 2000, amino acid residue G75 of the facilitative glucose transporter GLUT1 was identified by mutagenesis as being essential for transport function [Olsowski, A., et al. (2000) Biochemistry 39, 2469-74]. In 2002, we identified a heterozygous missense mutation substituting glycine at residue 75 for tryptophan in a 10-year-old girl with intractable seizures and low glucose concentrations in the cerebrospinal fluid indicative of GLUT1 deficiency. Glucose uptake into erythrocytes of the patient was 36% of controls, and GLUT1-specific immunoreactivity was normal, indicating a functional GLUT1 defect. In silico three-dimensional modeling of the G75W mutant provided a smaller gyration radius for transmembrane segment 2 as the potential pathogenic mechanism in this patient. This case illustrates a GLUT1 mutation characterized in vitro and later confirmed by disease itself and highlights the potential of basic science and clinical medicine to collaborate for the benefit of patients.

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Mining our ABCs: Pharmacogenomic approach for evaluating transporter function in cancer drug resistance.

Ross, DD & Doyle, LA, 2004. Cancer Cell 6(2):105-107

The association of transporter proteins and cancer drug resistance has been known for approximately 25 years, with recent discoveries pointing to an ever-increasing number of ATP binding cassette (ABC) transporter proteins involved with the response of cancer cells to pharmacotherapy. As reported in this issue of Cancer Cell, Szakacs et al. couple quantitative, real-time PCR assays for all 48 human ABC transporters with chemosensitivity information mined from the NCI-60 cancer cell line database. Predictions of transporter involvement in drug effect were validated in selected cases, and furthermore produced novel leads relating ABC transporter expression and chemoresistance or chemosensitivity

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Comment

An introductory comment for the following research article by Szakacs et al.

Predicting drug sensitivity and resistance: Profiling ABC transporter genes in cancer cells.

Szakacs, G. et al., 2004. Cancer Cell 6(2):129-137.

Abstract:

Multidrug resistance of tumors is frequently associated with decreased cellular accumulation of anticancer drugs and elevated expression of ABC transporters such as MDR1. At present, relatively little is known about the substrate specificities of most ABC transporters. Here, we present a pharmacogenomic approach, in which we correlate expression profiles of all 48 human ABC transporters with patterns of drug activity in the NCI-60 cell lines. The findings are used to identify candidate substrates for several ABC transporters, as well as compounds whose toxicities are potentiated by ABCB1-MDR1. The gene expression database will serve as a high-quality "time capsule" that can be mined to generate new hypotheses and to illuminate additional features of ABC transporters and their functional relationships with other molecules.

Journal Link  | PMID