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Sharon Marsh

Publications and source records attributed to Sharon Marsh.

At least 37 records · Page 2Linked to original sources
PubMed2005

Pharmacogenetics of colorectal cancer.

Colorectal cancer is one of the most common types of cancer in both men and women. Multiple chemotherapy combinations exist; however, there is currently no strategy for individualised therapy selection prior to treatment. Genetic polymorphisms in genes involved in the metabolism, transport or targets for the commonly used chemotherapy drugs (5-fluorouracil, irinotecan and oxaliplatin) have been described. Many require validation in large prospective trials before they can be used as markers for outcome and/or toxicity. This review describes the data available on polymorphisms in key genes that are associated with chemotherapy toxicity and response in colorectal cancer.

Animals↗
PubMed2005

Concordance of pharmacogenetic markers in germline and colorectal tumor DNA.

INTRODUCTION: Most cancer pharmacogenetic studies use germline DNA, as tumor tissue is often inaccessible in the advanced disease setting. However, this relies on the assumption that germline DNA is representative of the tumor genotype. To date, there has been little attention paid to defining the relationship between tumor and germline genomes. MATERIALS AND METHODS: This study compared 28 polymorphisms in 13 genes of high importance to cancer pharmacogenetics from ten different chromosome regions, in DNA from normal mucosa and colon tumors in 44 paired samples. RESULTS: 93% of samples had one or fewer genotype discrepancies. 77% of patients had intraindividual genotypes in complete concordance. In addition, although microsatellite instability (MSI) was identified in 20% of tumors, no significant association between MSI and genotype discrepancies was observed (p = 0.672). CONCLUSIONS: While this data validates the use of germline DNA pharmacogenetics in colorectal cancer, statistical analysis and modeling of pharmacogenetic data should be employed to incorporate this small, but important, source of error.

Colorectal Neoplasms↗
PubMed2004

ABCG2 pharmacogenetics: ethnic differences in allele frequency and assessment of influence on irinotecan disposition.

PURPOSE: The ATP-binding cassette transporter ABCG2 (breast cancer resistance protein) is an efflux protein that plays a role in host detoxification of various xenobiotic substrates, including the irinotecan metabolite 7- ethyl-10-hydroxycamptothecin (SN-38). The ABCG2 421C>A polymorphism has been associated with reduced protein expression and altered function in vitro. The aim of this study was to evaluate the ethnic distribution and potential functional consequence of the ABCG2 421C>A genotype in cancer patients treated with irinotecan. EXPERIMENTAL DESIGN: ABCG2 genotyping was performed using Pyrosequencing on DNA from 88 American Caucasians, 94 African Americans, 938 Africans, and 95 Han Chinese, as well as in 84 European Caucasian patients treated with irinotecan undergoing additional blood sampling for pharmacokinetic studies. RESULTS: Significant differences in allele frequencies were observed between the given world populations (P < 0.001), the variant allele being most common in the Han Chinese population with a frequency as high as 34%. The mean area under the curve of irinotecan and SN-38 were 19,851 and 639 ng x hour/mL, respectively. The frequency of the variant allele (10.7%) was in line with results in American Caucasians. No significant changes in irinotecan pharmacokinetics were observed in relation to the ABCG2 421C>A genotype, although one of two homozygous variant allele carriers showed extensive accumulation of SN-38 and SN-38 glucuronide. CONCLUSIONS: The ABCG2 421C>A polymorphism appears to play a limited role in the disposition of irinotecan in European Caucasians. It is likely that the contribution of this genetic variant is obscured by a functional role of other polymorphic proteins.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
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

Genotypes associated with myocardial infarction risk are more common in African Americans than in European Americans.

OBJECTIVES: This study was designed to describe the frequencies of multiple myocardial infarction (MI) risk-associated genotypes among different racial groups. BACKGROUND: Racial disparities in the prevalence of cardiovascular disease (CVD) are well known. Recent large Japanese case-control studies identified connexin-37 (GJA-4), plasminogen activator inhibitor-1 (PAI-1), and stromelysin-1 (MMP-3) polymorphisms as risk factors for MI, but the prevalence of these genotypes among different racial groups in the U.S. needs to be determined. METHODS: Genomic deoxyribonucleic acid from 95 healthy African Americans (AA) and 95 healthy European Americans (EA) was used for genotyping. Deoxyribonucleic acid containing the region of interest was amplified using the polymerase chain reaction, followed by genotyping using pyrosequencing. RESULTS: All three MI-risk genotypes were observed in both populations and were in Hardy-Weinberg equilibrium. The frequencies of two of the three "risk-associated" genotypes were significantly higher in the AA population: GJA4 C1019T T/T: AA, 20%, EA, 7% (p = 0.053); MMP3 -1171delA A/A: AA, 78%, EA, 24% (p < 0.001); PAI-1 -668delG G/G: AA, 55%, EA, 16% (p < 0.001). The likelihood of two or more high-risk genotypes was 3.3% among EA subjects and 51% in the AA group (p < 0.001). We found that 9.1% of AA had all three high-risk genotypes, compared with 0% among the EA group (p = 0.0097). CONCLUSIONS: We found higher frequencies of disease-associated genotypes in AA than in EA. Our results also show that more AA than EA carry multiple risk-associated genotypes. Future studies need to assess whether such genetic profiles predict adverse outcomes in U.S. populations and contribute to racial disparities in CVD burden.

Black or African American↗
PubMed2004

Diflomotecan pharmacokinetics in relation to ABCG2 421C>A genotype.

OBJECTIVE: The adenosine triphosphate-binding cassette transporter ABCG2 (breast cancer resistance protein [BCRP]) functions as an efflux transporter for many drugs, including the topoisomerase I inhibitor diflomotecan, and is expressed at high levels in the intestine and liver. We performed an exploratory analysis to evaluate the effects of the natural allelic variant ABCG2 421C>A on the pharmacokinetics of diflomotecan. METHODS: The drug was administered to 22 adult white patients with cancer as a 20-minute infusion (dose, 0.10-0.27 mg), followed 2 weeks later by an oral solution (dose, 0.10-0.35 mg). RESULTS: The ABCG2 421C>A genotype significantly affected the pharmacokinetics of diflomotecan; in 5 patients heterozygous for this allele, plasma levels after intravenous drug administration were 299% (P =.015) of those in 15 patients with wild-type alleles, at mean values of 138 ng x h/mL x mg(-1) (95% confidence interval, 11.3-264 ng x h/mL x mg(-1)) versus 46.1 ng x h/mL x mg(-1) (95% confidence interval, 25.6-66.7 ng x h/mL x mg(-1)), respectively. Diflomotecan levels were not significantly influenced by 11 known variants in the ABCB1, ABCC2, cytochrome P450 (CYP) 3A4, and CYP3A5 genes. CONCLUSION: These findings provide the first evidence linking variant ABCG2 alleles to altered drug exposure and suggest that interindividual variability in substrate drug effects might be influenced, in part, by ABCG2 genotype.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2004

Pharmacogenomic assessment of carboxylesterases 1 and 2.

Human carboxylesterases 1 and 2 (CES1 and CES2) catalyze the hydrolysis of many exogenous compounds. Alterations in carboxylesterase sequences could lead to variability in both the inactivation of drugs and the activation of prodrugs. We resequenced CES1 and CES2 in multiple populations (n = 120) to identify single-nucleotide polymorphisms and confirmed the novel SNPs in healthy European and African individuals (n = 190). Sixteen SNPs were found in CES1 (1 per 300 bp) and 11 in CES2 (1 per 630 bp) in at least one population. Allele frequencies and estimated haplotype frequencies varied significantly between African and European populations. No association between SNPs in CES1 or CES2 was found with respect to RNA expression in normal colonic mucosa; however, an intronic SNP (IVS10-88) in CES2 was associated with reduced CES2 mRNA expression in colorectal tumors. Functional analysis of the novel polymorphisms described in this study is now warranted to identify putative roles in drug metabolism.

Adult↗
PubMed2004

Pharmacogenetics of tipifarnib (R115777) transport and metabolism in cancer patients.

The purpose of this study was to perform exploratory relationships between the pharmacokinetics of the farnesyl transferase inhibitor, tipifarnib (R115777, Zarnestra) and allelic variants of genes coding for ATP binding-cassette transporters and drug-metabolizing enzymes. Twenty-eight patients with advanced solid tumors were treated with tipifarnib administered orally at a dose of 200 or 300 mg. Blood samples were collected for pharmacokinetics and genotyping of 10 variants in genes encoding P-glycoprotein (ABCB1), cytochrome P450 isozymes CYP3A4 and CYP3A5, and UDP glucuronosyltransferase isozyme UGT1A1. The homozygous T -allele of ABCB1*8 (1236C > T ) was associated with a trend for a higher area under the curve of tipifarnib as compared to patients with only one or no variant alleles [mean (+/-SD), 5,303 +/- 1,620 ng.h/mL vs. 3,619 +/- 1,275 ng.h/mL; P = 0.047). No statistically significant differences were observed with any other genetic variant ( P > 0.15). Overall, this study indicates that ABCB1 genotype might be correlated with tipifarnib pharmacokinetics, although considerable overlap in exposure measures between genotype groups was observed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

CYP3A5 polymorphism and the ethnic differences in cyclosporine pharmacokinetics in healthy subjects.

To determine the relationship between CYP3A5 polymorphism and cyclosporine pharmacokinetic parameters among healthy volunteers, an oral cyclosporine (CsA) pharmacokinetic study was performed in 16 healthy subjects. Blood CsA concentrations were measured by high-performance liquid chromatography. Concentration-versus-time data were analyzed by a noncompartmental method using WinNonLin, and the blood samples were genotyped for the CYP3A5 using the polymerase chain reaction and pyrosequencing. CsA pharmacokinetic parameters were dichotomized and compared using the 1-way ANOVA test according to the CYP3A5*3C genotype. There were 6 homozygous A/A (wild type), 6 homozygous G/G (variant), and 4 heterozygous A/G genotypes for CYP3A5*3 C in these 16 healthy volunteers. All whites were G/G group, and all African Americans except 1 were either A/A or A/G group. The mean AUC (ng x h/mL) of CsA for the 3 genotype groups were 4962 +/- 1074 (A/A), 6677 +/- 1153 (G/G), and 5416 +/- 1817 (A/G), (A/A versus G/G, P = 0.03), and the mean CL/F (mL/min/kg) were 15.6 +/- 3.1 (A/A), 12.0 +/- 2.3 (G/G), and 14.7 +/- 5.9 (A/G), (A/A versus G/G, P = 0.04). None of the other parameters were significantly different among the 3 genotypes. In conclusion, the CYP3A5*3C polymorphism appears to affect AUC and CL/F of oral CsA significantly in healthy subjects, which may partly explain some of the differences of pharmacokinetics in CsA between African Americans and whites.

Adolescent↗
PubMed2004

Frequency of compound genotypes associated with beta-blocker efficacy in congestive heart failure.

An important practical problem in pharmacogenetics is the integration of compound genotypes into individualized therapy. Polymorphisms in the genes encoding the angiotensin-converting enzyme, and beta(1)- and beta(2)-adrenoceptors have been identified as predictors of 'good response' to beta-adrenergic antagonists among heart failure patients. These variants were used as the basis for exploring the concept of compound genotype assessment. The frequency of compound variants in these genes was determined using PCR and pyrosequencing to genotype population samples of 95 African-Americans and 95 European-Americans. Both groups could be divided into four subgroups according to the number of favorable genotypes present. Each subgroup accounted for a significant proportion of subjects (the smallest was 7% of total). This study provides the first look into the population frequency of these compound genotypes, and it provides the necessary first step for future evaluation of polygenic strategies to individualize therapy for heart failure.

Adrenergic beta-Antagonists↗
PubMed2004

Single nucleotide polymorphism profiling across the methotrexate pathway in normal subjects and patients with rheumatoid arthritis.

Methotrexate (MTX) is a commonly used disease-modifying antirheumatic drug in rheumatoid arthritis (RA). Polymorphisms occur in several genes encoding key enzymes in the folic acid pathway, which is influenced by MTX, but have not been evaluated in patients with RA. The effect of race on allele frequency has also not been evaluated. In this study, the allele frequencies of polymorphisms in six key enzymes in the MTX-folate pathway in patients with RA and healthy controls, including several common racial groups were studied. European- and African-American patients with RA and European and African healthy controls were genotyped for 22 genetic loci in six genes in the MTX cellular pathway. Differences in genotype distributions between the different racial groups were evaluated using chi(2) tests. Allele frequencies were significantly different (p < 0.001) for eight single nucleotide polymorphisms between the European and African controls. The allele frequencies of two polymorphisms showed significant differences (p < 0.001) between the African- and European-American patients with RA. Thus, racial differences exist between the allele frequencies of several polymorphisms in enzymes in the MTX-folate pathway in patients with RA and healthy controls. Whether such differences contribute to a differential response to MTX in patients with RA deserves to be investigated.

Black or African American↗
PubMed2004

Pharmacogenetics of irinotecan toxicity.

Irinotecan is an anticancer drug approved in combination therapy for advanced colorectal cancer. Severe, life-threatening toxicities can occur from irinotecan treatment. Although multiple genes may play a role in irinotecan activity, the UDP glycuronosyltransferase 1 family, polypeptide A1 (UGT1A1) enzyme has been strongly associated with toxicity. A common dinucleotide repeat polymorphism in the UGT1A1 promoter region (UGT1A1*28) has been correlated with severe toxicity in cancer patients receiving irinotecan-containing therapy. Prospective screening of patients prior to chemotherapy selection may reduce the frequency of severe toxicities by allowing alternate therapy selections for patients carrying the UGT1A1*28 polymorphism.

Antineoplastic Agents, Phytogenic↗
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↗
PubMed2003

Ferredoxin reductase: pharmacogenomic assessment in colorectal cancer.

Ferredoxin reductase (FDXR) is a putative contributor to TP53-mediated apoptosis from 5-fluorouracil chemotherapy through the generation of oxidative stress. With TaqMan real-time quantitative reverse transcription-PCR, this study established a significant difference in FDXR relative RNA expression level between tumor (median, 212.9 units) and normal tissues (median, 113.8 units) from 51 colorectal cancer patients (P < 0.001). Seven single nucleotide polymorphisms (SNPs) in the FDXR gene were discovered, with no significant difference in variant allele frequency between colon tumor and normal tissues (P > 0.05), and the common haplotypes for FDXR were not different between colon tumor and normal samples. No correlation was observed between FDXR genotype and RNA expression implying that the polymorphisms described in this study are not regulating FDXR expression in colon cancer. This genomic characterization provides the foundation for pharmacogenetic analysis of the impact of FDXR on chemotherapy for colorectal cancer.

Adult↗
PubMed2003

Irinotecan pathway genotype analysis to predict pharmacokinetics.

PURPOSE: The purpose was to explore the relationships between irinotecan disposition and allelic variants of genes coding for adenosine triphosphate binding cassette transporters and enzymes of putative relevance for irinotecan. EXPERIMENTAL DESIGN: Irinotecan was administered to 65 cancer patients as a 90-min infusion (dose, 200-350 mg/m(2)), and pharmacokinetic data were obtained during the first cycle. All patients were genotyped for variants in genes encoding MDR1 P-glycoprotein (ABCB1), multidrug resistance-associated proteins MRP-1 (ABCC1) and MRP-2 (canalicular multispecific organic anion transporter; ABCC2), breast cancer resistance protein (ABCG2), carboxylesterases (CES1, CES2), cytochrome p450 isozymes (CYP3A4, CYP3A5), UDP glucuronosyltransferase (UGT1A1), and a DNA-repair enzyme (XRCC1), which was included as a nonmechanistic control. RESULTS: Eighteen genetic variants were found in nine genes of putative importance for irinotecan disposition. The homozygous T allele of the ABCB1 1236C>T polymorphism was associated with significantly increased exposure to irinotecan (P = 0.038) and its active metabolite SN-38 (P = 0.031). Pharmacokinetic parameters were not related to any of the other multiple variant genotypes, possibly because of the low allele frequency. The extent of SN-38 glucuronidation was slightly impaired in homozygous variants of UGT1A1*28, although differences were not statistically significant (P = 0.22). CONCLUSIONS: It is concluded that genotyping for ABCB1 1236C>T may be one of the factors assisting with dose optimization of irinotecan chemotherapy in cancer patients. Additional investigation is required to confirm these findings in a larger population and to assess relationships between irinotecan disposition and the rare variant genotypes, especially in other ethnic groups.

ATP Binding Cassette Transporter, Subfamily B, Mem↗