Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatic metastases occur in about half of patients with colorectal cancer. Since hepatic metastases are often not accessible for surgery, chemotherapy of metastases is important. The most commonly used chemotherapy drugs for hepatic metastases are fluorouracil, irinotecan, and oxaliplatin. Several enzymes are known to be involved in the catabolism and anabolism of these drugs, and the activity of these enzymes varies greatly between individuals. The causes of this variation include genetic polymorphisms, different regulation between normal and cancer tissue, and the influence of chemotherapy on enzyme expression. The varying enzyme activity may have an important effect on the outcome of chemotherapy. Several studies confirm the influence of the activity of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase on the outcome of fluorouracil therapy for colorectal cancer, with higher enzyme activities predicting lower treatment efficacy. Although fewer studies are available regarding therapy of hepatic metastases, the same relationship between thymidylate synthase activity and outcome of fluorouracil therapy observed for primary colorectal cancer was found. For the other two enzymes, only a few studies are available, but the results indicate similarly that higher enzyme activity seems to be disadvantageous. The enzymes responsible for the activation, metabolism and mechanism of action of irinotecan, namely carboxylesterase 2, cytochrome P450 (CYP) 3A4, uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1), and topoisomerase-I, also exhibit variable interindividual activity. Thus, there may be an association between enzyme activity and response to therapy. For instance, in patients with colorectal cancer, higher enzyme activity of topoisomerase-I seems to be predictive of a better response to irinotecan. CYP3A4 and UGT1A1 activity levels might be predictive of irinotecan toxicity rather than efficacy. The degradation of oxaliplatin is independent of potentially varying enzyme activity, but for this drug, the DNA repair enzyme ERCC1 may influence the survival time after chemotherapy. Taken together, the available data indicate the importance of the different enzyme activities on the outcome of chemotherapy of hepatic metastases in colorectal cancer. More information is needed, especially for the newer drugs irinotecan and oxaliplatin. However, the existing data are very promising in respect to the potential to guide dose and drug selection for more efficient and less toxic chemotherapy of hepatic metastases.
 ...
PMID:Pharmacogenomics of fluorouracil, irinotecan, and oxaliplatin in hepatic metastases of colorectal cancer: clinical implications. 1572 86

Enzymatic activation of irinotecan (CPT-11) is due to carboxylesterase (CES), and its pharmacological behavior is influenced by drug resistance-related proteins. We previously reported that the clinical response and prognosis of metastatic colorectal cancer (mCRC) patients did not differ in tumors with different thymidylate synthase (TS) or topoisomerase-I (Topo-I) expression. Using immunohistochemistry (IHC), we evaluated the biological role of CES2 and the expression of breast cancer resistance protein (BCRP/ABCG2) in 58 consecutive mCRC patients, who had undergone a first-line CPT-11/5-FU/leucovirin (FOLFIRI) regimen. The expression of these proteins was also examined in a group of synchronous lymph nodes and liver metastases. Furthermore, all samples were revaluated for TS and Topo-I expression. High expression of CES2, ABCG2, TS and Topo-I was observed in 55%, 56%, 38% and 49% of patients, respectively. There was a significant association between high TS and high ABCG2 expression (p = 0.049). Univariate analysis showed that only TS expression significantly impacted on time to progression (p = 0.005). Moreover, Cox' multivariate analysis revealed that TS expression was significantly associated with overall survival (p = 0.01). No significant correlation was found between investigated markers expression and clinical response. Topo-I expression resulted in being significantly higher in liver metastases with respect to the corresponding primary tumors (p < 0.0001), emphasizing the role of Topo-I expression in metastatic cancer biology. In primary tumor tissues, CES2 expression tended to be higher than that observed in liver metastasis tissues (p = 0.05). These preliminary data may suggest CES2 over-expression as a potential marker of malignant phenotype. In light of these findings, we suggest that Topo-I expression together with TS expression could be associated with metastatic progression of CRC. Further studies are warranted with the aim of evaluating the potential predictive and prognostic role of CES2 and ABCG2 in larger series of patients.
...
PMID:CES2, ABCG2, TS and Topo-I primary and synchronous metastasis expression and clinical outcome in metastatic colorectal cancer patients treated with first-line FOLFIRI regimen. 2519