Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

UDP glucuronosyltransferase (UGT) 1A1 gene promoter polymorphism can affect the expression level of the UGT 1A1 enzyme. The polymorphism consists of an insertion of a TA nucleotide sequence into a (TA)6TAA sequence in the gene promoter resulting in (TA)7TAA (UGT1A1*28). This results in a reduced UGT 1A1 expression with 70% less glucuronidation capacity for bilirubin and other UGT1A1 substrates. Other polymorphisms include (TA)8TAA (UGT1A1*37) and (TA)5TAA (UGT1A1*36). The longer the TA repeats the lower the enzyme expression level. The anticancer agent irinotecan is metabolized to the active SN-38, which is further glucuronidated and detoxified by UGT 1A1. Decreased glucuronidation leads to SN-38 accumulation with severe neutropenia and diarrhea. We have developed a rapid polymerase chain reaction (PCR)-based detection of all length polymorphisms in the UGT 1A1 gene promoter. It uses PCR and DNA fragment analysis using an ABI Genetic Analyzer. Thirty-two blood samples were analyzed for UGT 1A1 promoter polymorphism. We found 2 (TA)(5)TAA/(TA)(5)TAA, 4 (TA)(5)TAA/(TA)(6)TAA, 2 (TA)(5)TAA/(TA)(7)TAA, 9 (TA)(6)TAA/(TA)(6)TAA, 11 (TA)(6)TAA/(TA)(7)TAA, 2 (TA)(7)TAA/(TA)(7)TAA, and 2 (TA)(7)TAA/(TA)(8)TAA in our sample group. To confirm the results, 6 samples with different repeats were also analyzed by DNA sequencing method. This is a rapid and reliable method for analysis of the promoter length polymorphisms of UGT 1A1 gene.
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PMID:Validation of rapid polymerase chain reaction-based detection of all length polymorphisms in the UGT 1A1 gene promoter. 1747 Nov 58

Recent pharmacogenetic studies on irinotecan have revealed the impact of UDP glucuronosyltransferase (UGT) 1A1*28 on severe irinotecan toxicities. Although the clinical role of UGT1A1*6, which is specifically detected in East Asian patients, in irinotecan toxicities is suggested, clear evidence remains limited. To examine the impact of *6, the association of UGT1A1 genotypes with severe irinotecan toxicities was retrospectively investigated in Japanese cancer patients. A significant *6-dependent increase in the incidence of grade 3 or 4 neutropenia was observed in 49 patients on irinotecan monotherapy (p=0.012). This study further clarifies the clinical importance of *6 in irinotecan therapy in East Asians.
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PMID:Importance of UDP-glucuronosyltransferase 1A1*6 for irinotecan toxicities in Japanese cancer patients. 1808 37

The concept of the UDP glucuronosyltransferase family 1 member A1 genotype-directed schedule of irinotecan administration is still far from being introduced into clinical practice, and the efficacy and toxicity of irinotecan are in part schedule-dependent. The objective of the present meta-analysis was to determine the efficacy and adverse effects of 3-weekly vs. weekly irinotecan for the treatment of solid tumors. The PubMed, EMBASE and Cochrane Library databases and the search engines Google Scholar and Medical Martix were searched for randomized controlled trials to compare the two regimens of irinotecan administration. The results of the meta-analysis indicated that the 3-weekly regimen yielded a longer time to progression, while other measures of efficacy, such as the objective response rate and overall survival of patients with solid tumors were similar between the two regimens of irinotecan administration. Furthermore, the group receiving the 3-weekly regimen had a lower incidence of grade 3/4 diarrhea and a higher rate of grade 3/4 neutropenia compared with the group receiving the weekly regimen. However, these results require confirmation by large-sample, multicenter, randomized, controlled trials.
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PMID:Different schedules of irinotecan administration: A meta-analysis. 2744 80

Irinotecan-induced severe neutropenia and diarrhea, which remain unpredictable, has restrained the dose and clinical efficiency of irinotecan administration. In the present study, a total of 70 irinotecan-treated patients with histologically confirmed metastatic gastrointestinal cancer were enrolled. Despite genotyping well-reported alleles, direct sequencing was specifically adopted to avoid ethnic heterogeneity and to identify novel variations. The promoter (-1000 bp) and exon 1 regions of UDP glucuronosyltransferase family 1 member A complex locus (UGT1A1) gene family members UGT1A1, UGT1A7 and UGT1A9 were sequenced, and comprehensive analysis of their genetic polymorphisms was performed to determine the association between inherited genetic variations and irinotecan-induced toxicity. A total of 23 different genetic variants were detected in the present study, including 2 novel polymorphisms. The results of the present study revealed that UGT1A1*6 and UGT1A7*3 are risk factors for irinotecan-induced severe neutropenia, and UGT1A9*1b is associated with severe diarrhea. These results may provide biomarkers for the selection of the optimal chemotherapy for Chinese patients with metastatic gastrointestinal cancer.
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PMID:UGT1A1*6, UGT1A7*3 and UGT1A9*1b polymorphisms are predictive markers for severe toxicity in patients with metastatic gastrointestinal cancer treated with irinotecan-based regimens. 2789 97