A Carboxylesterase 2 Gene Polymorphism as Predictor of Capecitabine on Response and Time to Progression

Ribelles, Nuria; Lopez-Siles, J.; Sánchez, A.; Gonzalez, E.; Sánchez, Marta; Carabantes, F.; Sánchez‐Rovira, Pedro; Márquez, Ana; Dueñas, Rosario; Sevilla, Isabel; Alba, Emilio

doi:10.2174/138920008784220646

Cited by 61 publications

(28 citation statements)

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“…Fitzgerald and colleagues (10) reported a difference in CDD expression considering haplotypes containing rs602950 and rs532545, but because this haplotype is very rare (!1%) in our series of patients and in cell lines, it cannot account for the differences in expression observed. To our knowledge, only Ribelles and colleagues (9) have analyzed the association between the rs3215400 CDD polymorphism and HFS, but not significant correlation was found. Because of the limited sample size in the study of Ribelles and colleagues, their negative result could be a consequence of a lack of statistical power.…”

Section: Discussionmentioning

confidence: 85%

A Polymorphism in the Cytidine Deaminase Promoter Predicts Severe Capecitabine-Induced Hand-Foot Syndrome

Caronia

Martín

Sastre

et al. 2011

Clinical Cancer Research

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Purpose: Hand-foot syndrome (HFS) is one of the most relevant dose-limiting adverse effects of capecitabine, an oral prodrug of 5-fluorouracil used in the standard treatment of breast and colorectal cancer. We investigated the association between grade 3 HFS and genetic variations in genes involved in capecitabine metabolism.Experimental Design: We genotyped a total of 13 polymorphisms in the carboxylesterase 2 (CES2) gene, the cytidine deaminase (CDD) gene, the thymidine phosphorylase (TP) gene, the thymidylate synthase (TS) gene, and the dihydropyrimidine dehydrogenase (DPD) gene in 130 patients treated with capecitabine. We correlated these polymorphisms with susceptibility to HFS.Results: We found an association of HFS appearance with rs532545 located in the promoter region of CDD (OR ¼ 2.02, 95% CI ¼ 1.02-3.99, P ¼ 0.039). Because we found no association between the rs532545 genotype and CDD mRNA expression in Epstein-Barr virus lymphoblastoid cells, we explored additional genetic variations across the CDD promoter. We found an insertion, rs3215400, in linkage disequilibrium with rs532545 (D 0 ¼ 0.92), which was more clearly associated with HFS (OR ¼ 0.51, 95% CI ¼ 0.27-0.95, P ¼ 0.028) in patients and with total CDD gene expression (P ¼ 0.004) in lymphoblastoid cells. In silico analysis suggested that this insertion might create a binding site for the transcriptional regulator E2F. Using a SNaPshot assay in lymphoblastoid cells, we observed a 5.7-fold increased allele-specific mRNA expression from the deleted allele. Conclusions:The deleted allele of rs3215400 shows an increased allele-specific expression and is significantly associated with an increased risk of capecitabine-induced HFS.

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Section: Discussionmentioning

confidence: 85%

A Polymorphism in the Cytidine Deaminase Promoter Predicts Severe Capecitabine-Induced Hand-Foot Syndrome

Caronia

Martín

Sastre

et al. 2011

Clinical Cancer Research

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“…22) It is also noteworthy that there is a significant association between SNP in the 5′-untranslated region of the CES2 gene and both response rate and time to progression after capecitabine therapy, although its relevance to HFS is unknown. 23) Further studies should be needed for exploring biomarkers for HFS/efficacy to realize personalized capecitabine therapy.…”

Section: Discussionmentioning

confidence: 99%

Significant Association between Hand-Foot Syndrome and Efficacy of Capecitabine in Patients with Metastatic Breast Cancer

Azuma¹,

Hata

Sai³

et al. 2012

Biological & Pharmaceutical Bulletin

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Capecitabine, an oral prodrug of 5-fluorouracil (5-FU), is a promising treatment for colorectal, breast and gastric cancers, but often causes hand-foot syndrome (HFS), the most common dose-limiting toxicity. The current study was conducted to investigate the relationship between HFS and efficacy of capecitabine in 98 patients with metastatic breast cancer. Possible associations between HFS and efficacy endpoints, including time-to-treatment failure (TTF), tumor response in metastatic lesions and changes in tumor markers, were investigated retrospectively using electronic medical records. The TTF of group with HFS of grade 1 and ≥2 was significantly longer than that of group with no HFS, respectively (hazard ratio (HR), 0.39; 95% confidence interval (CI), 0.18-0.87 for group with grade 1; HR, 0.42, 95% CI, 0.19-0.90 for group with grade ≥2). Significantly higher disease control rates for the liver metastasis were observed in patients with HFS (grade 1 and greater) than in those without HFS (92.9 vs. 42.9%, p 0.009). Furthermore, prevention of increases in tumor marker levels (carcinoembryonic antigen (CEA), carbohydrate antigen 15-3 (CA15-3) and National Cancer Center-Stomach-439 (NCC-ST439)) was evident in patients with HFS. This study clearly showed a significant correlation between HFS and some efficacy markers of capecitabine therapy in patients with metastatic breast cancer, and suggests that early dose adjustment based on severity of HFS might improve efficacy. Studies are needed to explore predictive biomarkers for HFS/efficacy, so that capecitabine therapy can be further tailored to patient response.Key words capecitabine; hand-foot syndrome; efficacy; electronic medical record Capecitabine is administered as an oral fluoropyrimidine prodrug in the treatment of a number of cancers, including breast and gastrointestinal cancers. 1) Capecitabine generates 5-fluorouracil (5-FU) preferentially in tumor tissue through a three-step enzymatic process. In the first step, capecitabine is hydrolyzed by carboxylesterase (CES) in the liver to produce the 5′-deoxy-5-fluorocytidine (5′-DFCR). In the second step, 5′-DFCR is converted to 5′-deoxy-5-fluorouridine (5′-DFUR) by cytidine deaminase (CDA), which is highly active in liver and tumor tissues.2) In the final step, 5′-DFUR is converted to 5-FU by thymidine phosphorylase (TP), a rate-limiting enzyme. Dihydropyrimidine dehydrogenase (DPYD), a ratelimiting catabolic enzyme of the pyrimidines, is also involved in the degradation pathway of capecitabine.1,3) Since TP activity is 3-10 times higher in tumor cells than in the normal tissues, 2,4) selective conversion of capecitabine to 5-FU in tumor tissues minimizes systemic exposure to 5-FU relative to exposures associated with intravenous (i.v.) 5-FU/leukovorin regimens. Thus, capecitabine is associated with a lesser incidence of 5-FU-related severe toxicities, such as diarrhea, stomatitis, nausea, alopecia and neutropenia, while maintaining equivalent or superior efficacy compared with the IV regimens. 5-7)The most com...

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“…CES1 is primarily expressed in the liver, where it plays an important role in the metabolism of many prescribed medications including clopidogrel (Kazui et al, 2010;Hagihara et al, 2009) and methylphenidate (Nemoda et al, 2009). CES2 is present predominately in the intestine, where it has been shown to hydrolyze anticancer prodrugs gemcitabine (Pratt et al, 2013), capecitabine (Ribelles et al, 2008), and irinotecan. (Humerickhouse et al, 2000).…”

Section: Determining Relative Role Of Carboxylesterase Ces1 and Ces2mentioning

confidence: 99%

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions--an Industry Perspective

Bohnert¹,

Patel²,

Templeton³

et al. 2016

Drug Metabolism and Disposition

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Under the guidance of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), scientists from 20 pharmaceutical companies formed a Victim Drug-Drug Interactions Working Group. This working group has conducted a review of the literature and the practices of each company on the approaches to clearance pathway identification (f CL ), estimation of fractional contribution of metabolizing enzyme toward metabolism (f m ), along with modeling and simulation-aided strategy in predicting the victim drug-drug interaction (DDI) liability due to modulation of drug metabolizing enzymes. Presented in this perspective are the recommendations from this working group on: 1) strategic and experimental approaches to identify f CL and f m , 2) whether those assessments may be quantitative for certain enzymes (e.g., cytochrome P450, P450, and limited uridine diphosphoglucuronosyltransferase, UGT enzymes) or qualitative (for most of other drug metabolism enzymes), and the impact due to the lack of quantitative information on the latter. Multiple decision trees are presented with stepwise approaches to identify specific enzymes that are involved in the metabolism of a given drug and to aid the prediction and risk assessment of drug as a victim in DDI. Modeling and simulation approaches are also discussed to better predict DDI risk in humans. Variability and parameter sensitivity analysis were emphasized when applying modeling and simulation to capture the differences within the population used and to characterize the parameters that have the most influence on the prediction outcome.

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A Carboxylesterase 2 Gene Polymorphism as Predictor of Capecitabine on Response and Time to Progression

Cited by 61 publications

References 45 publications

A Polymorphism in the Cytidine Deaminase Promoter Predicts Severe Capecitabine-Induced Hand-Foot Syndrome

A Polymorphism in the Cytidine Deaminase Promoter Predicts Severe Capecitabine-Induced Hand-Foot Syndrome

Significant Association between Hand-Foot Syndrome and Efficacy of Capecitabine in Patients with Metastatic Breast Cancer

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions--an Industry Perspective

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