H L McLeod

..The number specifies the key mutation and, where appropriate, a letter following the number indicates an additional mutation on the mutant allele. Criteria for classification as a distinct allele are also presented...

..This study demonstrates rapid systemic clearance of AG2034 and suggests pharmacokinetic approaches that may minimize patient toxicity and aid the development of this interesting class of anticancer agents...

..This study confirms ethnic differences in the predominant mutant TPMT allele and the findings will be useful for the development of polymerase chain reaction-based strategies to prevent toxicity with thiopurine medications...

..This study demonstrates that 11.6% of the children had variant TPMT alleles. Prospective identification of TPMT genotype may be a promising tool for decreasing excessive haematological toxicity in individuals with low activity...

..Erythrocyte COMT activity was lower and less thermostable in individuals with homozygous low activity alleles. The data provide molecular evidence that low COMT is less common in African individuals than the Caucasian population...

..The presence of nonlinear docetaxel pharmacokinetics at doses above 115 mg/m2 will have to be determined in case of further dose escalation...

..These data emphasize the complex nature of the molecular mechanisms controlling polymorphic DPD activity in vivo...

..This is a unique example suggesting the influence of multiple selection pressures within individual populations. Hum Mutat 16:528, 2000...

..These studies highlight the need to combine DPD genotype and phenotype analysis to identify mutations that result in reduced enzyme activity...

..05 in each case), suggesting that c-erbB-2 is not a prognostic marker in colorectal cancer...

..Further insight into regulation of DPD expression may identify new avenues for the treatment of clinical problems associated with DPD deficiency...

..These results suggest that a broad spectrum MMP inhibitor is worthy of evaluation as a therapeutic method of reducing tumor invasion and metastasis in stage II NSCLC...

..The high frequency of the C allele in the African group implies overexpression of PGP and may have important therapeutic and prognostic implications for use of PGP dependent drugs in individuals of African origin...

..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...

..This is consistent with previous studies where higher TS expression was associated with poor response to TS inhibitors. Prospective analysis of the influence of the TS polymorphism on patient outcome is warranted...

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..This study is the first to indicate that the presence of CYP1B1 in cells decreases their sensitivity to the cytotoxic effects of a specific anticancer drug...

..This study provides the first analysis of TPMT mutant allele frequency in an African population and indicates that, unlike Caucasians, TPMT*3C is the most common allele in African subjects...

..05). These results indicate that while EGFR overexpression is a common event in colorectal carcinogenesis, it does not influence patient prognosis...

..In addition, PCNA-labeling indices between paired samples were neither consistently higher nor lower, suggesting that the proliferative capacity of tumor cells is not directly related to their ability to metastasize...

..TPMT*2 appears to be a more recent allele, which has only been detected in Caucasians to date. These ethnic differences may be important in the clinical use of thiopurine drugs...

..The novel regions of instability identified within the tumor genome may contribute toward the unique tumor phenotype and relative chemoresistance...

..The high tumor:normal tissue ratio supports further interest in base excision repair, through UDG, as a potential source of fluoropyrimidine resistance in colorectal cancer...

..The AG2034 AUC(0-24)increased by a median of 184% (range 20-389%) from cycle 1 to 3 in all 10 patients examined. No objective antitumour responses were observed in the study...

..The results obtained indicate that several anticancer agents inhibit CYP1B1 activity. Drug inactivation by CYP1B1 may represent a novel mechanism of resistance, influencing the clinical outcome of chemotherapy...

..As a large degree of the variation in tumour DPD activity is not explained by PMNC activity, more accurate alternatives are needed before DPD activity can be used for targeting 5-FU therapy...

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..43; 95% CI=0.99-11.77). While independent confirmation is required in further studies, these results provide a potential tool to assist prediction strategies for this important disease...

..This suggests the presence of co-ordinated regulation of these pyrimidine metabolic enzymes and offers a strategy for optimising the use of pyrimidine-based chemotherapy...

..These data provide encouragement that comprehensive transcript analysis will aid the quest for more enlightened therapeutics...

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..We detected no mutations in the 606 alleles studied and conclude that mutations at codon 974 are a rare event...

..Additional investigations may shed light on the mechanistic impact of the mitotic spindle checkpoint pathway in colorectal tumor initiation and progression...

..005 Spearman's rank correlation test). In contrast no detectable CYP1B1 was found in normal ovary...

..CONCLUSION: A method for performing two dimensional gel electrophoresis and mass spectrometry using laser capture microdissected tissue has been developed...

..7% in European-Americans was corrected to 0%. The comprehensible and reliable genotyping method developed in this study would be useful to evaluate associations between the genotype and phenotype...

..The allele frequency was different from that in Caucasians, and investigation of TPMT polymorphisms with consideration of ethnic differences before administration of azathioprine or 6MP may provide clinically useful information...

..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...

..Understanding the influence of ethnicity on pharmacogenomics will allow for comprehensive strategies for using the genome to optimize therapy for patients throughout the world...

..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...

..Likewise, DFS may be decreased in patients with mucinous tumours who receive 5-FU. The presence of mucin should be carefully evaluated in developmental trials of new agents for treating colorectal cancer...

..Although the relative mRNA levels compared to beta-actin measured with competitive template RT-PCR were different from the data obtained with a TaqMan based PCR, a significant correlation between the two assays was found...

..This information on ERCC2 genomic structure will allow the construction of definitive studies to clarify the clinical role of this important gene...

..We report that Cox-1 and Cox-2 expression is highly variable in Dukes' C tumours, and changes in Cox-1 expression may be of importance...

..05). This study provides the first step to identify markers for predicting variability in gemcitabine response and toxicity...

..In addition, the need for polygenic pharmacogenomic strategies to identify patients at risk for adverse drug reactions will be highlighted...

..This profound change in haplotype frequencies from Africans to non-Africans supports a possible bottleneck during the dispersion of modern humans from Africa...

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