The mRNA and protein expression of thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) and their relationship with prognosis were investigated. Real-time quantitative RT-P...The mRNA and protein expression of thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) and their relationship with prognosis were investigated. Real-time quantitative RT-PCR (Taqman) was used to detect the mRNA expression of TS, TP and DPD in formalin-fixed and paraffin-embedded 106 samples of epithelial ovarian cancer and 29 normal ovaries. A TATA box-binding protein (TBP) was used as an endogenous reference gene. A relationship between TS, TP, DPD expression and clinicopathologic features was investigated. The protein location and expression of TS, TP and DPD was examined in the same patients by an avidin-biotin-peroxidase immunohistochemistry. TS and TP mRNA expression levels were significantly higher in tumor group than in normal controls, with the average value of TS and TP mRNA being 6.14±0.62 and 0.59±0.06 in tumor tissue, and 0.71±0.14 and 0.16±0.04 in normal tissue, respectively. DPD mRNA expression levels were significantly lower in tumor group (0.11±0.02) than in normal controls (0.38±0.05). There was statistically significant difference in TS and TP mRNA expression levels among different pathological grades and clinical stages (P<0.05), but histological subtype was not significantly associated with TS and TP mRNA expression. DPD gene expression was not significantly associated with any clinicopathological parameters. Immunohistochemistry revealed that TP protein was mainly distributed in nucleus, and TS and DPD mainly in cytoplasm. The protein expression intensity of TS, TP and DPD was coincided with the mRNA expression levels. It was concluded that TS, TP mRNA and protein expression levels were significantly higher in epithelial ovarian cancer, and DPD mRNA and protein expression levels were significantly lower. The expression levels of TS and DPD were related to the patients’ prognosis and survival. Combined gene expression levels of TS, TP and DPD represent a new variable to predict the clinical outcome in ovarian cancer. The association of TS, TP and DPD expression levels with survival suggests an importance of these genes for tumor occurrence and progression.展开更多
Background Dihydropyrimidine dehydrogenase （DPD）, a key enzyme involved in the catabolism of 5-fluorouracil （5-FU）, is the attractive candidate for pharmacogenetic research on efficacies and toxicities of 5-FU. Th...Background Dihydropyrimidine dehydrogenase （DPD）, a key enzyme involved in the catabolism of 5-fluorouracil （5-FU）, is the attractive candidate for pharmacogenetic research on efficacies and toxicities of 5-FU. The aim of this study is to explore the association between polymorphisms of dihydropyrimidine dehydrogenase gene （DPYD） and clinical outcomes of gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy in the Chinese population.展开更多
Fluoropyrimidines are widely used in the treatment of solid tumors, mainly gastrointestinal, head and neck and breast cancer. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for catabolism of 5-FU an...Fluoropyrimidines are widely used in the treatment of solid tumors, mainly gastrointestinal, head and neck and breast cancer. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for catabolism of 5-FU and it is encoded by DPYD gene. To date, many known polymorphisms cause DPD deficiency and subsequent increase of 5-FU toxicity. In addition, reduced inactivation of 5-FU could lead to increased 5-FU intracellular concentration and augmented efficacy of this drugs. Therefore DPD expression, particularly intratumoral, has been investigated as predictive and prognostic marker in 5-FU treated patients. There also seems to be a tendency to support the correlation between DPD expression and response/survival in patients treated with fluoropyrimidine even if definitive conclusions cannot be drawn considering that some studies are conflicting. Therefore, the debate on intratumoral DPD expression as a potential predictor and prognostic marker in patients treated with fluoropyrimidines is still open. Four DPD-polymorphisms are the most relevant for their frequency in population and clinical relevance. Many studies demonstrate that treating a carrier of one of these polymorphisms with a full dose of fluoropyrimidine can expose patient to a severe, even life-threatening, toxicity. Severe toxicity is reduced if this kind of patients received a dose-adjustment after being genotyped. CPIC (Clinical Pharmacogenetics Implementation Consortium) is an International Consortium creating guidelines for facilitating use of pharmacogenetic tests for patient care and helps clinicians ensuring a safer drug delivery to the patient. Using predictive DPD deficiency tests in patients receiving 5FU-based chemotherapy, in particular for colorectal cancer, has proven to be a cost-effective strategy.展开更多
There are differences between African-American and white patients with colorectal cancer, concerning their characteristics before and after diagnosis. Whites are more likely to adhere to screening guidelines. This is ...There are differences between African-American and white patients with colorectal cancer, concerning their characteristics before and after diagnosis. Whites are more likely to adhere to screening guidelines. This is also the case among people with positive family history. Colorectal cancer is more frequent in Blacks. Studies have shown that that since 1985, colon cancer rates have dipped 20% to 25% for Whites, while rates have gone up for African-American men and stayed the same for African-American women. Overall, African-Americans are 38% to 43% more likely to die from colon cancer than are Whites. Furthermore, it seems that there is an African-American predominance in right-sited tumors. African Americans tend to be diagnosed at a later stage, to suffer from better differentiated tumors, and to have worse prognosis when compared with Whites. Moreover, less black patients receive adjuvant chemotherapy for resectable colorectal cancer or radiation therapy for rectal cancer. Caucasians seem to respond better to standard chemotherapy regimens than AfricanAmericans. Concerning toxicity, it appears that patients of African-American descent are more likely to develop 5-FU toxicity than Whites, possibly because of their different dihydropyridine dehydrogenase status. Last but not least, screening surveillance seems to be higher among white than among black long-term colorectal cancer survivors. Socioeconomic and educational status account for most of these differences whereas little evidence exists for a genetic contribution in racial disparity. Understanding the nature of racial differences in colorectal cancer allows tailoring of screening and treatment interventions.展开更多
The treatment scenario of colorectal cancer(CRC)has been evolving in recent years with the introduction of novel targeted agents and new therapeutic strategies for the metastatic disease.An extensive effort has been d...The treatment scenario of colorectal cancer(CRC)has been evolving in recent years with the introduction of novel targeted agents and new therapeutic strategies for the metastatic disease.An extensive effort has been directed to the identification of predictive biomarkers to aid patients selection and guide therapeutic choices.Pharmacogenomics represents an irreplaceable tool to individualize patients treatment based on germline and tumor acquired somatic genetic variations able to predict drugs response and risk of toxicities.The growing knowledge of CRC molecular characteristics and complex genomic makeup has played a crucial role in identifying predictive pharmacogenomic biomarkers,while supporting the rationale for the development of new drugs and treatment combinations.Clinical validation of promising biomarkers,however,is often an issue.More recently,a deeper understanding of resistance mechanisms and tumor escape dynamics under treatment pressure and the availability of novel technologies are opening new perspectives in this field.This review aims to present an overview of current pharmacogenomic biomarkers and future perspectives of pharmacogenomics in CRC,in an evolving scenario moving from a single drug-gene interactions approach to a more comprehensive genome-wide approach,comprising genomics and epigenetics.展开更多
基金supported by a grant from the National Natural Sciences Foundation of China (No. 30973184)
文摘The mRNA and protein expression of thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) and their relationship with prognosis were investigated. Real-time quantitative RT-PCR (Taqman) was used to detect the mRNA expression of TS, TP and DPD in formalin-fixed and paraffin-embedded 106 samples of epithelial ovarian cancer and 29 normal ovaries. A TATA box-binding protein (TBP) was used as an endogenous reference gene. A relationship between TS, TP, DPD expression and clinicopathologic features was investigated. The protein location and expression of TS, TP and DPD was examined in the same patients by an avidin-biotin-peroxidase immunohistochemistry. TS and TP mRNA expression levels were significantly higher in tumor group than in normal controls, with the average value of TS and TP mRNA being 6.14±0.62 and 0.59±0.06 in tumor tissue, and 0.71±0.14 and 0.16±0.04 in normal tissue, respectively. DPD mRNA expression levels were significantly lower in tumor group (0.11±0.02) than in normal controls (0.38±0.05). There was statistically significant difference in TS and TP mRNA expression levels among different pathological grades and clinical stages (P<0.05), but histological subtype was not significantly associated with TS and TP mRNA expression. DPD gene expression was not significantly associated with any clinicopathological parameters. Immunohistochemistry revealed that TP protein was mainly distributed in nucleus, and TS and DPD mainly in cytoplasm. The protein expression intensity of TS, TP and DPD was coincided with the mRNA expression levels. It was concluded that TS, TP mRNA and protein expression levels were significantly higher in epithelial ovarian cancer, and DPD mRNA and protein expression levels were significantly lower. The expression levels of TS and DPD were related to the patients’ prognosis and survival. Combined gene expression levels of TS, TP and DPD represent a new variable to predict the clinical outcome in ovarian cancer. The association of TS, TP and DPD expression levels with survival suggests an importance of these genes for tumor occurrence and progression.
文摘Background Dihydropyrimidine dehydrogenase （DPD）, a key enzyme involved in the catabolism of 5-fluorouracil （5-FU）, is the attractive candidate for pharmacogenetic research on efficacies and toxicities of 5-FU. The aim of this study is to explore the association between polymorphisms of dihydropyrimidine dehydrogenase gene （DPYD） and clinical outcomes of gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy in the Chinese population.
文摘Fluoropyrimidines are widely used in the treatment of solid tumors, mainly gastrointestinal, head and neck and breast cancer. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for catabolism of 5-FU and it is encoded by DPYD gene. To date, many known polymorphisms cause DPD deficiency and subsequent increase of 5-FU toxicity. In addition, reduced inactivation of 5-FU could lead to increased 5-FU intracellular concentration and augmented efficacy of this drugs. Therefore DPD expression, particularly intratumoral, has been investigated as predictive and prognostic marker in 5-FU treated patients. There also seems to be a tendency to support the correlation between DPD expression and response/survival in patients treated with fluoropyrimidine even if definitive conclusions cannot be drawn considering that some studies are conflicting. Therefore, the debate on intratumoral DPD expression as a potential predictor and prognostic marker in patients treated with fluoropyrimidines is still open. Four DPD-polymorphisms are the most relevant for their frequency in population and clinical relevance. Many studies demonstrate that treating a carrier of one of these polymorphisms with a full dose of fluoropyrimidine can expose patient to a severe, even life-threatening, toxicity. Severe toxicity is reduced if this kind of patients received a dose-adjustment after being genotyped. CPIC (Clinical Pharmacogenetics Implementation Consortium) is an International Consortium creating guidelines for facilitating use of pharmacogenetic tests for patient care and helps clinicians ensuring a safer drug delivery to the patient. Using predictive DPD deficiency tests in patients receiving 5FU-based chemotherapy, in particular for colorectal cancer, has proven to be a cost-effective strategy.
文摘There are differences between African-American and white patients with colorectal cancer, concerning their characteristics before and after diagnosis. Whites are more likely to adhere to screening guidelines. This is also the case among people with positive family history. Colorectal cancer is more frequent in Blacks. Studies have shown that that since 1985, colon cancer rates have dipped 20% to 25% for Whites, while rates have gone up for African-American men and stayed the same for African-American women. Overall, African-Americans are 38% to 43% more likely to die from colon cancer than are Whites. Furthermore, it seems that there is an African-American predominance in right-sited tumors. African Americans tend to be diagnosed at a later stage, to suffer from better differentiated tumors, and to have worse prognosis when compared with Whites. Moreover, less black patients receive adjuvant chemotherapy for resectable colorectal cancer or radiation therapy for rectal cancer. Caucasians seem to respond better to standard chemotherapy regimens than AfricanAmericans. Concerning toxicity, it appears that patients of African-American descent are more likely to develop 5-FU toxicity than Whites, possibly because of their different dihydropyridine dehydrogenase status. Last but not least, screening surveillance seems to be higher among white than among black long-term colorectal cancer survivors. Socioeconomic and educational status account for most of these differences whereas little evidence exists for a genetic contribution in racial disparity. Understanding the nature of racial differences in colorectal cancer allows tailoring of screening and treatment interventions.
文摘The treatment scenario of colorectal cancer(CRC)has been evolving in recent years with the introduction of novel targeted agents and new therapeutic strategies for the metastatic disease.An extensive effort has been directed to the identification of predictive biomarkers to aid patients selection and guide therapeutic choices.Pharmacogenomics represents an irreplaceable tool to individualize patients treatment based on germline and tumor acquired somatic genetic variations able to predict drugs response and risk of toxicities.The growing knowledge of CRC molecular characteristics and complex genomic makeup has played a crucial role in identifying predictive pharmacogenomic biomarkers,while supporting the rationale for the development of new drugs and treatment combinations.Clinical validation of promising biomarkers,however,is often an issue.More recently,a deeper understanding of resistance mechanisms and tumor escape dynamics under treatment pressure and the availability of novel technologies are opening new perspectives in this field.This review aims to present an overview of current pharmacogenomic biomarkers and future perspectives of pharmacogenomics in CRC,in an evolving scenario moving from a single drug-gene interactions approach to a more comprehensive genome-wide approach,comprising genomics and epigenetics.
