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Biomedical subjects

Cristi R King

Publications and source records attributed to Cristi R King.

6 recordsLinked to original sources
PubMed2007

Pyrosequencing: a simple method for accurate genotyping.

Pharmacogenetic research benefits first-hand from the abundance of information provided by the completion of the Human Genome Project. With such a tremendous amount of data available comes an explosion of genotyping methods. Pyrosequencing is one of the most thorough yet simple methods to date used to analyze polymorphisms. It also has the ability to identify tri-allelic, indels, short-repeat polymorphisms, along with determining allele percentages for methylation or pooled sample assessment. In addition, there is a standardized control sequence that provides internal quality control. This method has led to rapid and efficient single-nucleotide polymorphism evaluation including many clinically relevant polymorphisms. The technique and methodology of Pyrosequencing is explained in this chapter.

DNA Primers↗
PubMed2006

Disposition of 9-nitrocamptothecin and its 9-aminocamptothecin metabolite in relation to ABC transporter genotypes.

PURPOSE: The source of the pharmacokinetic variability of 9-nitrocamptothecin (9NC) and its 9-aminocamptothecin (9AC) metabolite is unknown. ATP-binding cassette (ABC) transporters have been reported to modulate camptothecin analogues, are associated with camptothecin resistance, and might also affect 9NC and 9AC pharmacokinetics. The aim of this study was to evaluate the functional consequence of known single nucleotide polymorphisms in the transporter genes ABCB1, ABCC2, and ABCG2 on the pharmacokinetic disposition of 9NC and 9AC. EXPERIMENTAL DESIGN: Pharmacokinetic and genotyping studies were performed in 55 patients as part of two phase I studies of 9NC in patients with refractory solid tumors, a phase II study of 9NC in patients with advanced colon cancer, and a study evaluating the disposition of 9NC after administration of a single dose under fasting conditions. DNA was isolated from plasma and analyzed for variants in ABCB1, ABCC2, and ABCG2 genes. The ABCB1 1236C>T (n = 43), ABCB1 2677G>T/A (n = 43), ABCB1 3435C>T (n = 43), ABCC2 3972C>T (n = 39), and ABCG2 421C>A (n = 42) variants were analyzed using Pyrosequencing. RESULTS: The ABCG2 421C>A genotype significantly affected the pharmacokinetics of 9AC. The mean 9AC lactone AUC/dose for wild-type (n = 25) and heterozygous (n = 2) patients were 14.3 ng/mL x h and 51.1 ng/mL x h, respectively (P = 0.032). The mean +/- SD 9AC total AUC/dose for wild-type (n = 39) and heterozygous (n = 3) patients were 91.9 +/- 78.3 ng/mL x h and 129.0 +/- 90.5 ng/mL x h, respectively (P = 0.40). 9NC and 9AC disposition were not significantly influenced by variants in ABCB1, ABCC2, and ABCG2, and ABCB1 and ABCC2, respectively (P > 0.05). CONCLUSION: These findings suggest that inter-individual variability in 9AC disposition, but not 9NC, may be influenced, in part, by ABCG2 genotype. In contrast, there was no evidence for a relationship between ABCG2 and the disposition of 9NC, or for relationships between ABCB1 and ABCC2 genotypes and the disposition of 9NC or 9AC.

ATP-Binding Cassette Transporters↗
PubMed2005

Pyrosequencing of clinically relevant polymorphisms.

The data generated from the Human Genome Project has led to an explosion of technology for low-, medium-, and high-throughput genotyping methods. Pyrosequencing is a genotyping assay based on sequencing by synthesis. Short runs of sequence around each polymorphism are generated, allowing for internal controls for each sample. Pyrosequencing can also be used to identify tri-allelic, indel, and short-repeat polymorphisms, as well as determining allele percentages for methylation or pooled sample assessment. Assays details for Pyrosequencing of clinically relevant polymorphisms are described in this chapter.

Adenosine Triphosphate↗
PubMed2004

Distribution of ITPA P32T alleles in multiple world populations.

Dose-limiting toxicity from azathioprine treatment affects up to 37% of patients. Screening for thiopurine methyltransferase (TPMT) polymorphisms will prospectively identify approximately 10% of patients. Recently, a polymorphism in the inosine triphosphate pyrophosphatase gene (ITPA) has been associated with severe azathioprine toxicity. We demonstrate here that this proline to threonine substitution at codon 32 in the ITPA gene is found at low frequency in Central/South American populations (1-2%), at a constant frequency across Caucasian and African populations (6-7%), and is highest in Asian populations (14-19%). This data is consistent with previously described allele frequencies in other Caucasian (7%), African (5%), and Asian (11-15%) populations. This data provides a foundation on which prospective screening studies can be planned to identify patients at risk for severe toxicity from azathioprine therapy.

Alleles↗
PubMed2004

Application of pharmacogenomics in the individualization of chemotherapy for gastrointestinal malignancies.

The large number of active combination chemotherapy regimens for the treatment of gastrointestinal cancers has led to the need for better information to guide the "standard" treatment for each patient. In an attempt to individualize therapy, pharmacogenomics evaluates the hereditary basis for interindividual differences in drug response. This report will focus on the results of studies assessing the effects of polymorphisms in drug-metabolizing enzymes and drug targets on the toxicity and response to chemotherapy drugs commonly used to treat gastrointestinal malignancies.

Antimetabolites, Antineoplastic↗