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Biomedical subjects

S Marsh

Publications and source records attributed to S Marsh.

At least 19 recordsLinked to original sources
PubMed2007

Pharmacogenetic analysis of paclitaxel transport and metabolism genes in breast cancer.

Paclitaxel is commonly used in the treatment of breast cancer. Variability in paclitaxel clearance may contribute to the unpredictability of clinical outcomes. We assessed genomic DNA from the plasma of 93 patients with high-risk primary or stage IV breast cancer, who received dose-intense paclitaxel, doxorubicin and cyclophosphamide. Eight polymorphisms in six genes associated with metabolism and transport of paclitaxel were analyzed using Pyrosequencing. We found no association between ABCB1, ABCG2, CYP1B1, CYP3A4, CYP3A5 and CYP2C8 genotypes and paclitaxel clearance. However, patients homozygous for the CYP1B1*3 allele had a significantly longer progression-free survival than patients with at least one Valine allele (P=0.037). This finding could reflect altered paclitaxel metabolism, however, the finding was independent of paclitaxel clearance. Alternatively, the role of CYP1B1 in estrogen metabolism may influence the risk of invasive or paclitaxel resistant breast cancer in patients carrying the CYP1B1*3 allele.

Adult↗
PubMed2007

Variants in the SLCO1B3 gene: interethnic distribution and association with paclitaxel pharmacokinetics.

To explore retrospectively the relationships between paclitaxel pharmacokinetics and three known, non-synonymous single-nucleotide polymorphisms (SNPs) in SLCO1B3, the gene encoding organic anion transporting polypeptide (OATP)1B3. Accumulation of [(3)H]paclitaxel was studied in Xenopus laevis oocytes injected with cRNA of Oatp1b2, OATP1A2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, and NTCP. The 334T>G (Ser112Ala), 699G>A (Met233Ile), and 1564G>T (Gly522Cys) loci of SLCO1B3 were screened in 475 individuals from five ethnic groups and 90 European Caucasian cancer patients treated with paclitaxel. Only OATP1B3 was capable of transporting paclitaxel to a significant extent (P=0.003). The 334T>G and 699G>A SNPs were less common in the African-American and Ghanaian populations (P<0.000001). Paclitaxel pharmacokinetics were not associated with the studied SNPs or haplotypes (P>0.3). The studied SNPs in SLCO1B3 appear to play a limited role in the disposition of paclitaxel, although their clinical significance in other ethnic populations remains to be investigated.

Animals↗
PubMed2007

Irinotecan-induced diarrhea: functional significance of the polymorphic ABCC2 transporter protein.

Interindividual pharmacokinetic variability of the anticancer agent irinotecan is high. Life-threatening diarrhea is observed in up to 25% of patients receiving irinotecan and has been related with irinotecan pharmacokinetics and UGT1A1 genotype status. Here, we explore the association of ABCC2 (MRP2) polymorphisms and haplotypes with irinotecan disposition and diarrhea. A cohort of 167 Caucasian cancer patients who were previously assessed for irinotecan pharmacokinetics (90-min infusion given every 21 days), toxicity, and UGT1A1*28 genotype were genotyped for polymorphisms in ABCC2 using Pyrosequencing. Fifteen ABCC2 haplotypes were identified in the studied patients. The haplotype ABCC2*2 was associated with lower irinotecan clearance (28.3 versus 31.6 l/h; P=0.020). In patients who did not carry a UGT1A1*28 allele, a significant reduction of severe diarrhea was noted in patients with the ABCC2*2 haplotype (10 versus 44%; odds ratio, 0.15; 95% confidence interval, 0.04-0.61; P=0.005). This effect was not observed in patients with at least one UGT1A1*28 allele (32 versus 20%; odds ratio, 1.87; 95% confidence interval, 0.49-7.05; P=0.354). This study suggests that the presence of the ABCC2*2 haplotype is associated with less irinotecan-related diarrhea, maybe as a consequence of reduced hepatobiliary secretion of irinotecan. As the association was seen in patients not genetically predisposed at risk for diarrhea due to UGT1A1*28, confirmatory studies of the relationships of ABCC2 genotypes and irinotecan disposition and toxicity are warranted.

Adult↗
PubMed2006

Ethnic differences in pharmacogenetically relevant genes.

There is great heterogeneity in the way humans respond to medications, often requiring empirical strategies to define the appropriate drug therapy for each patient. Genetic polymorphisms in drug metabolizing enzymes, transporters, receptors, and other drug targets provide putative markers for predicting which patients will experience extreme toxicity and treatment failure. Both quantitative (allele frequency) and qualitative (specific allele) differences for polymorphic genes have been observed between different population groups. For example, the frequency of mutations in thiopurine methyltransferase is lower in Chinese than Caucasian populations. In addition, the predominant mutation responsible for deficient enzyme activity differs between the two populations (TPMT*l3C versus TPMT*3A). Understanding the influence of ethnicity on pharmacogenomics will allow for comprehensive strategies for using the genome to optimize therapy for patients throughout the world.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2005

Interethnic variability of ERCC2 polymorphisms.

Excision Repair Cross-Complementing Rodent Repair Group 2 (ERCC2) plays an important role in DNA repair by eliminating bulky DNA adducts produced by platinum agents during the nucleotide excision repair pathway. Several studies have associated polymorphisms in ERCC2 with response to platinum therapy, lung cancer risk, and DNA repair capacity. This study examined ERCC2 polymorphisms and haplotype structure across 18.9 kb in 95 European, 95 African, and 95 Asian individuals. Single-nucleotide polymorphisms (SNPs) (ERCC2 -9164 A>T, -1989 A>G, -516 G>A, 468 C>A [Arg156Arg], 1737 C>T [Val579Val], 2133 C>T [Asp711Asp], and 2251 T>G [Lys751Gln]) were mined and mapped using Golden Path, PolyMAPr, and Promolign. Genotyping was performed using PCR and pyrosequencing. Allele frequencies ranged from 0 to 0.47 (Europeans), 0.05 to 0.72 (Africans), and 0 to 0.47 (Asians). The synonymous cSNP at codon 579 could not be confirmed in our populations. There were significant differences in haplotype structure and frequency between populations. This information on ERCC2 genomic structure will allow the construction of definitive studies to clarify the clinical role of this important gene.

Adult↗
PubMed2005

Comparison of fatalities from work related motor vehicle traffic incidents in Australia, New Zealand, and the United States.

OBJECTIVE: To compare the extent and characteristics of motor vehicle traffic incidents on public roads resulting in fatal occupational injuries in Australia, New Zealand (NZ), and the United States (US). DESIGN AND SETTING: Information came from separate data sources in Australia (1989--92), NZ (1985--98), and the US (1989--92). METHODS: Using data systems based on vital records, distributions and rates of fatal injuries resulting from motor vehicle traffic incidents were compared for the three countries. Common inclusion criteria and occupation and industry classifications were used to maximize comparability. RESULTS: Motor vehicle traffic incident related deaths accounted for 16% (NZ), 22% (US), and 31% (Australia) of all work related deaths during the years covered by the studies. Australia had a considerably higher crude rate (1.69 deaths/100,000 person years; 95% confidence interval (95% CI) 1.54 to 1.83) compared with both NZ (0.99; 95% CI 0.85 to 1.12) and the US (0.92; 95% CI 0.89 to 0.94). Industry distribution differences accounted for only a small proportion of this variation in rates. Case selection issues may have accounted for some of the remainder, particularly in NZ. In all three countries, male workers, older workers, and truck drivers were at higher risk. CONCLUSIONS: Motor vehicle traffic incidents are an important cause of work related death of workers in Australia, NZ, and the US. The absolute rates appear to differ between the three countries, but most of the incident characteristics were similar. Lack of detailed data and inconsistencies between the data sets limit the extent to which more in-depth comparisons could be made.

Accidents, Occupational↗
PubMed2004

Cancer pharmacogenetics.

The large number of active combination chemotherapy regimens for most cancers has led to the need for better information to guide the 'standard' treatment for each patient. In an attempt to individualise therapy, pharmacogenetics and pharmacogenomics (a polygenic approach to pharmacogenetic studies) encompass the search for answers to the hereditary basis for interindividual differences in drug response. This review will focus on the results of studies assessing the effects of polymorphisms in drug-metabolising enzymes and drug targets on the toxicity and response to commonly used chemotherapy drugs. In addition, the need for polygenic pharmacogenomic strategies to identify patients at risk for adverse drug reactions will be highlighted.

Antineoplastic Agents↗
PubMed2004

Identification and analysis of single-nucleotide polymorphisms in the gemcitabine pharmacologic pathway.

Significant variability in the antitumor efficacy and systemic toxicity of gemcitabine has been observed in cancer patients. However, there are currently no tools for prospective identification of patients at risk for untoward events. This study has identified and validated single-nucleotide polymorphisms (SNP) in genes involved in gemcitabine metabolism and transport. Database mining was conducted to identify SNPs in 14 genes involved in gemcitabine metabolism. Pyrosequencing was utilized to determine the SNP allele frequencies in genomic DNA from European and African populations (n=190). A total of 14 genetic variants (including 12 SNPs) were identified in eight of the gemcitabine metabolic pathway genes. The majority of the database variants were observed in population samples. Nine of the 14 (64%) polymorphisms analyzed have allele frequencies that were found to be significantly different between the European and African populations (P<0.05). This study provides the first step to identify markers for predicting variability in gemcitabine response and toxicity.

Antimetabolites, Antineoplastic↗
PubMed2004

Polymorphism of the thymidylate synthase gene and thymidylate synthase levels in colon cancer cell lines and different tissues of colorectal cancer patients.

In a panel of 18 colon cancer cell lines we found that the thymidylate synthase (TS) genotype was related to TS enzyme activity, but not to TS protein and mRNA levels. In addition, no relation with drug sensitivity was observed. TS genotyping of different tissues from 78 colorectal cancer patients revealed a high level of homology in polymorphic status between normal and malignant tissues and the heterozygous genotype to be the most frequent.

Antimetabolites, Antineoplastic↗
PubMed2003

Detection of disease-specific PrP in the distal ileum of cattle exposed orally to the agent of bovine spongiform encephalopathy.

The immunohistochemical localisation of the disease-specific protein, PrP(Sc), was examined in the distal ileum of cattle up to 40 months after they had been exposed orally to the agent of bovine spongiform encephalopathy (BSE), in the intestines and mesenteric lymph nodes of an additional group of cattle, killed six months after a similar exposure, and in the distal ileum of naturally occurring clinical cases of BSE. PrP(Sc) was detected, mainly in macrophages, in a small proportion of the follicles of Peyer's patches in the distal ileum of the experimentally exposed cattle throughout much of the course of the disease. The observations are in agreement with the infectivity data derived from mouse bioassays of the distal ileum. At the later stages of the disease, the proportion of immunostained follicles increased as the total number of follicles decreased with age. In the additional experimental group of cattle, PrP(Sc) was confined to the Peyer's patches in the distal ileum. No immunostaining was detected in the lymphoid tissue of the distal ileum of naturally occurring clinical cases of BSE. In some of the clinically affected experimentally induced and naturally occurring cases of BSE there was sparse immunostaining of the neurons of the distal ileal myenteric plexus.

Aging↗
PubMed2002

Induction of thymidylate synthase as a 5-fluorouracil resistance mechanism.

Thymidylate synthase (TS) is a key enzyme in the de novo synthesis of 2'-deoxythymidine-5'-monophosphate (dTMP) from 2'-deoxyuridine-5'-monophosphate (dUMP), for which 5,10-methylene-tetrahydrofolate (CH(2)-THF) is the methyl donor. TS is an important target for chemotherapy; it is inhibited by folate and nucleotide analogs, such as by 5-fluoro-dUMP (FdUMP), the active metabolite of 5-fluorouracil (5FU). FdUMP forms a relatively stable ternary complex with TS and CH(2)THF, which is further stabilized by leucovorin (LV). 5FU treatment can induce TS expression, which might bypass dTMP depletion. An improved efficacy of 5FU might be achieved by increasing and prolonging TS inhibition, a prevention of dissociation of the ternary complex, and prevention of TS induction. In a panel of 17 colon cancer cells, including several variants with acquired resistance to 5FU, sensitivity was related to TS levels, but exclusion of the resistant variants abolished this relation. For antifolates, polyglutamylation was more important than the intrinsic TS level. Cells with low p53 levels were more sensitive to 5FU and the antifolate raltitrexed (RTX) than cells with high, mutated p53. Free TS protein down-regulates its own translation, but its transcription is regulated by E2F, a cell cycle checkpoint regulator. Together, this results in low TS levels in stationary phase cells. Although cells with a low TS might theoretically be more sensitive to 5FU, the low proliferation rate prevents induction of DNA damage and 5FU toxicity. TS levels were not related to polymorphisms of the TS promoter. Treatment with 5FU or RTX rapidly induced TS levels two- to five-fold. In animal models, 5FU treatment resulted in TS inhibition followed by a two- to three-fold TS induction. Both LV and a high dose of 5FU not only enhanced TS inhibition, but also prevented TS induction and increased the antitumor effect. In patients, TS levels as determined by enzyme activity assays, immunohistochemistry and mRNA expression, were related to a response to 5FU. 5FU treatment initially decreased TS levels, but this was followed by an induction, as seen with an increased ratio of TS protein over TS-mRNA. The clear retrospective relation between TS levels and response now forms the basis for a prospective study, in which TS levels are measured before treatment in order to determine the treatment protocol.

Animals↗
PubMed2001

Colorectal cancer genomics: evidence for multiple genotypes which influence survival.

Colorectal cancer (CRC) is a leading cause of cancer death and the mechanism for variable outcome in this disease is not yet fully understood. It is hypothesized that differences in the genetic make-up of tumours may be partially responsible for the differences observed in survival among same staged individuals for this disease. In this study the tumour genomes of 29 consecutive patients undergoing surgery for Dukes' C CRC were assessed by comparative genomic hybridization (CGH). In addition, the CGH profiles from the tumours were compared with those from eight colorectal cell lines. Great variation in genetic grade (all detectable aberrations i.e., loss + gain) was observed in 29 Dukes' C colorectal tumours by CGH (median four aberrations per tumour, range 0-20). Gain was found in 76% and loss in 41% of tumours. The most frequently observed regions of gain were 13q (27.6%), 20q (27.6%), 7p (24.1%), 8q (24.1%), and 1q (20.7%) and loss were 18q (31%), 4q (20.7%), 17p (20.7%), 18p (20.7%), and 15q (20.1%). None of these specific genomic aberrations were associated with patient survival. However, patients with more than two aberrations had a better survival than patients with fewer regions of loss and gain (P = 0.02). CRC cell lines had similar regions of loss or gain as the tumours. However, the frequency of genomic aberrations was much greater in the CRC cell lines. Although genomic change in CRC is relevant to the survival of patients with Dukes' C CRC, careful analysis is required to identify cell lines which are representative models of CRC genomics.

Aged↗
PubMed2001

Pharmacogenomic dissection of resistance to thymidylate synthase inhibitors.

Chemoresistance is a major obstacle for successful cancer treatment. Gene amplification and altered expression are the main genetic mechanisms of tumor chemoresistance. Previously, only a limited number of genes were analyzed in each individual study using traditional molecular methods such as Northern and Southern blotting. In this study, the global gene expression patterns of 1176 genes in a panel of five thymidylate synthase (TS) inhibitor [raltitrexed (TDX) and 5-fluorouracil (5-FU)] resistant and sensitive parent cell lines were investigated using cDNA array technology. Only 28 of 1176 genes were altered >1.5-fold among resistant cells, with 2 genes (TS and YES1) consistently higher in the panel. TS mRNA and protein were consistently overexpressed in all drug-resistant tumor cell lines compared with the sensitive parent cell lines. Southern blot and FISH analysis demonstrated that the TS gene was amplified in 5-FU- and TDX-resistant cell lines. YES1 mRNA and protein were overexpressed in four drug-resistant tumor cell lines but were not overexpressed in the lymphoblast cell line W1L2(TDX), although the YES1 gene was highly amplified in these cells. The fact that W1L2 has high level (>10-fold) resistance to TS inhibitor in the absence of high YES1 expression leads to a conclusion that YES1 has no direct role in this drug resistance process. By narrowing the search from 1176 to 2 genes, the analysis of in vitro TDX and 5-FU resistance becomes more straightforward for confirmatory studies. These data provide encouragement that comprehensive transcript analysis will aid the quest for more enlightened therapeutics.

Blotting, Northern↗
PubMed2001

Thymidylate synthase pharmacogenetics in colorectal cancer.

Thymidylate synthase (TS) is an important target for chemotherapy drugs, such as 5-fluorouracil (5-FU), 5-fluorodeoxyuridine (FUDR), oral 5-FU prodrugs (e.g., uracil/tegafur [UFT], S-1, and capecitabine), and other novel folate-based drugs (e.g., raltitrexed, pemetrexed, and nolatrexed). Overexpression of TS is linked to resistance to TS-targeted chemotherapy drugs. Polymorphic tandem repeats located in the TS enhancer region (TSER) have been shown to influence TS expression. Three copies (TSER*3) of the tandem repeat give a 2.6-fold greater in vitro TS expression than 2 copies (TSER*2). A stepwise increase in expression and enzyme activity has been observed with increasing copies of the TSER. Alleles containing 4 (TSER*4), 5 (TSER*5), and 9 (TSER*9) copies of the tandem repeat have also been identified, although the effect of these alleles remains unclear. Preliminary data have suggested that stage III colorectal cancer patients with the TSER*3/TSER*3 genotype do not receive the improvement in survival from adjuvant 5-FU observed in patients with the TSER*3/TSER*2 or TSER*2/TSER*2 genotype. A poor response rate to 5-FU for neoadjuvant rectal or metastatic colorectal disease is also apparent in TSER*3/TSER*3 patients. This has significant clinical implications because TSER*3/TSER*3 occurs in 30% of Caucasian patients. Ethnic variation also exists in the TSER, with Asian populations having significantly higher frequency of TSER*3 than other world populations. Prospective confirmation of the impact of TSER on outcome, after TS-targeted chemotherapy, will define the utility of pharmacogenetics to optimize the selection of 5-FU therapy for colorectal cancer.

Antimetabolites, Antineoplastic↗