Dihydropyrimidine Dehydrogenase Levels in Colorectal Cancer Cells Treated with a Combination of Heat Shock Protein 90 Inhibitor and Oxaliplatin or Capecitabine (original) (raw)
Related papers
Differences in Dihydropyrimidine Dehydrogenase Activities Between Gastric and Colorectal Cancer
Digestive Diseases and Sciences, 2000
We studied the relation between clinicopathological factors and dihydropyrimidine dehydrogenase (DPD) activity in gastric and colorectal carcinomas. Specimens obtained by surgery from 27 gastric and 17 colorectal carcinomas and their normal mucosa were examined. The levels of DPD activity in the gastric carcinomas and their normal mucosa were significantly higher than those in colorectal carcinomas and their normal counterparts, respectively (both P's < 0.0001). The gastric carcinomas had significantly higher DPD activities than their normal mucosa (P = 0.028), but the colorectal carcinomas did not. Among the clinicopathological factors, which included invasion/metastatic status and staging, the only effect was that of the histological differences of gastric cancer on DPD activity. That is, the level of DPD activity of the histologically undifferentiated gastric carcinoma was significantly higher than that of the differentiated type. No prognostic predictive values of DPD were recognized in either gastric and colorectal cancer. In conclusion, the higher DPD activity in gastric cancer than colorectal cancer may be due to the higher DPD activity in the background mucosa of origin, and the higher population of undifferentiated type of histological classification, compared to the colorectal counterparts.
Annals of Oncology, 2005
Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are essential enzymes for 5-fluorouracil (5-FU) metabolism. In patients with advanced colorectal cancer (ACRC), retrospective studies have shown that low expression levels of TS and DPD correlated with response to 5-FU. We performed a prospective study in which the choice of first-line chemotherapy with either 5-FU or a non-5-FU containing regimen was based on TS and DPD expression. Fresh-frozen samples of metastases were obtained from 58 previously untreated patients with ACRC. mRNA expression of TS and DPD was quantified using an RT-PCR assay. Patients with low tumor expression of both TS and DPD received weekly bolus 5-FU/leucovorin (LV) 500 mg/m2 (group A); patients with high TS and/or DPD received 3-weekly oxaliplatin 85 mg/m2 and irinotecan 200 mg/m2 (group B). After progression, cross-over to the alternative regimen was attempted. Of 53 eligible patients, 31 had tumors with both low TS and low DPD, and were treated in group A. A response was observed in 11 patients [35%; 95% confidence interval (CI) 19% to 54%]. Cross-over to second-line oxaliplatin/irinotecan resulted in a partial response in two out of 16 patients (13%; 95% CI 1% to 38%). In group B, four out of 22 patients responded (18%; 95% CI 5% to 40%), while no responses were observed in 12 patients after cross-over to 5-FU/LV (0%; 95% CI 0% to 28%). Prospective selection of 5-FU/LV chemotherapy based on low TS and DPD expression in patients with ACRC did not confirm the high response rates reported in retrospective studies. The procedure of obtaining metastatic tissue and quantitation of enzymes appeared feasible but cumbersome. Before assessing the clinical utility of a predictive marker in a randomized trial, future studies should focus on prospective validation of the assay in a large and well defined population.
Journal of Molecular Biomarkers & Diagnosis
Gastrointestinal toxicity due to chemotherapeutic drugs is a common problem in cancer patients. Chemotherapy-related diarrhea is most commonly described with fluoropyrimidines (fluorouracil and capecitabine) and irinotecan. Fluoropyrimidines are widely used for the treatment of gastrointestinal (GI) tract tumors and also in other solid malignancies such as breast and head and neck cancers [1,2] and are relatively well tolerated, however, around 5% to 10% of the treated patients develops severe, potentially life threatening toxicity such as GI toxicity, skin toxicity, myelosuppression and neurotoxicity [3]. Early identification of patients at risk of developing fluoropyrimidines-induced toxicity by upfront screening might allow dose reduction or selection of an alternative chemotherapy regimen. The two well-studies predictive markers for fluoropyrimidines-related toxicity are dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) enzymatic activity.
Bioorganic & Medicinal Chemistry Letters, 2003
A series of tumor-activated prodrugs of the inhibitors of dihydropyrimidine dehydrogenase (DPD), an enzyme catabolizing 5-fluorouracil (5-FU: 4g), has been designed and synthesized. RO0094889 (11c) is a prodrug of 5-vinyluracil (4c), a known DPD inhibitor, and was designed to generate 4c selectively in tumor tissues by sequential conversion of 11c by three enzymes: esterase, cytidine deaminase and thymidine phosphorylase, the latter two of which are known to be highly expressed in various tumor tissues. When capecitabine (1), a tumor-activated prodrug of 5-FU, was co-administered orally with 11c, 5-FU in tumor tissues was significantly increased with only a slight increase of 5-FU in plasma as compared with oral capecitabine alone.
Clinical colorectal cancer, 2006
Fluoropyrimidine drugs such as 5-fluorouracil (5-FU) and capecitabine are a mainstay in the treatment of numerous solid tumors, including colorectal cancers, alone or as part of combination therapies. Cytotoxic drugs such as 5-FU and oral capecitabine display narrow therapeutic indexes combined with high interpatient pharmacokinetic variability. As a result, severe toxicities often limit or delay the administration of successive, optimal chemotherapeutic courses, leading to unfavorable clinical outcome in patients with cancer. Catabolism and deactivation of fluoropyrimidine drugs depend on a single and exclusive enzymatic step driven by dihydropyrimidine dehydrogenase (DPD). Dihydropyrimidine dehydrogenase is prone to marked circadian rhythms, drug-drug interactions, and genetic polymorphisms; influence of its erratic activity on 5-FU pharmacokinetics and toxicity profile has been extensively investigated, and it is now well known that DPD deficiency leads to severe toxicities with ...
2014
At present, fluoropyrimidine, based on 5-fluorouracil (5-FU), remains one of the most frequently prescribed chemotherapeutics drugs for the treatment of cancer. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the catabolism of 5-FU, and DPD enzymatic activities are usually varied dramatically from individual to individual, including both the intrapatient differences and the interpatient variability. There is a certain correlation between the DPD activity and efficacy and toxicity following the administration of fluoropyrimidine drugs. Partial or complete loss of DPD activity can lead to serious or even lethal toxicity. In this article, we review the relationship between DPD activity and efficacy and toxicity following the administration of fluoropyrimidine drugs, and also the structure, function, and characteristics of DPD. We report here that measurement of DPD activity may become a strategy and be paid much attention to predict the efficacy and toxicity prior ...
Dihydropyrimidine dehydrogenase in the metabolism of the anticancer drugs
Cancer Chemotherapy and Pharmacology, 2019
Cancer caused by fundamental defects in cell cycle regulation leads to uncontrolled growth of cells. In spite of the treatment with chemotherapeutic agents of varying nature, multiple resistance mechanisms are identified in cancer cells. Similarly, numerous variations, which decrease the metabolism of chemotherapeutics agents and thereby increasing the toxicity of anticancer drugs have been identified. 5-Fluorouracil (5-FU) is an anticancer drug widely used to treat many cancers in the human body. Its broad targeting range is based upon its capacity to act as a uracil analogue, thereby disrupting RNA and DNA synthesis. Dihydropyrimidine dehydrogenase (DPD) is an enzyme majorly involved in the metabolism of pyrimidines in the human body and has the same metabolising effect on 5-FU, a pyrimidine analogue. Multiple mutations in the DPD gene have been linked to 5-FU toxicity and inadequate dosages. DPD inhibitors have also been used to inhibit excessive degradation of 5-FU for meeting appropriate dosage requirements. This article focusses on the role of dihydropyrimidine dehydrogenase in the metabolism of the anticancer drug 5-FU and other associated drugs.
Therapeutic advances in medical oncology, 2012
The objective of this study was to evaluate the safety of using tegafur-uracil (UFT) in colorectal cancer patients with partial dihydropyrimidine dehydrogenase (DPD) deficiency. The study included five colorectal cancer patients who presented with acute toxicity (grades 3 and 4) after being given the first cycle of chemotherapy using 5-fluorouracil. The DPD deficiency was confirmed by gene sequencing. After a full recovery from all side effects, we changed the regimen to UFT (300 mg/m(2)/day) associated with leucovorin (90 mg/day) for 21 days, with an empirical dose reduction of at least 10% in the first cycle. We prospectively analysed 22 UFT cycles in 5 patients. We did not observe any episodes of grade 3 or 4 toxicity. The predominant toxicities were of grades 1 and 2 (nausea, vomiting and diarrhoea). Here, we demonstrate a complete absence of severe toxicity in all patients and cycles analysed. We believe that UFT is a safe alternative for the treatment of patients with partial ...