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)

The combination of irinotecan (Camptosar), epirubicin, and capecitabine (Xeloda) has shown an acceptable toxicity profile. In this open-label phase I study, irinotecan was administered IV at a fixed dose of 250 mg/m2 on day 1 in combination with capecitabine at a fixed dose of 1500 mg/m2 for days 2 to 7 and epirubicin starting at a dose of 40 mg/m2 and escalating by 10 mg/m2 in cohorts of three patients for those with metastatic adenocarcinomas. With the addition of granulocyte colony-stimulating factor (G-CSF [Neupogen]) to the regimen, patients received epirubicin at clinically relevant doses after dose-escalation. Results of the topoisomerase activity will be reported with the final results of this phase I study. The dose-limiting toxicity has not yet been reached. This combination regimen in patients with upper gastrointestinal malignancies and breast cancer will be investigated as part of phase II studies, once the dose-limiting toxicity is determined. The appropriate sequencing of the regimen to maximize clinical efficacy will also be determined.
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PMID:Irinotecan, epirubicin, and capecitabine in metastatic adenocarcinomas: preliminary results of a phase I study. 1568 35

Current treatment modalities for cancer combine cytotoxic drugs against DNA and novel targeted drugs affecting signal transduction pathways, which are required for growth progression and metastasizing tumors. Classical chemotherapeutic regimens for gastro-intestinal tumors include antimetabolites based on 5-fluorouracil (5FU), the platinum analog oxaliplatin and the topoisomerase inhibitor irinotecan. The thymidine analog trifluorothymidine (TFT) has been shown to bypass resistance pathways for 5FU derivatives (S-1, UFT, Xeloda) in model systems, while concurrent application with a thymidine phosphorylase inhibitor (TPI) increases the bioavailability of TFT, thereby potentiating the in vivo efficacy of TFT. The formulation TAS-102 is given orally in a 1.0:0.5 molar ratio (TFT:TPI). The formulation is dual-targeted due to the cytotoxic effect of TFT, which is enhanced by TPI, while TPI also exerts antiangiogenic effects by inhibiting thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor. Evidence is accumulating from in vitro and in vivo preclinical studies that these properties favor further combinations with other cytotoxic agents currently being used in the treatment of gastro-intestinal tumors. Also treatment with targeted agents will synergistically down-regulate signal transduction pathways responsible for growth and progression of tumors. In this review, we summarize the available information on (clinical) pharmacology, mechanisms of action, pharmacodynamic and pharmacokinetic properties, early clinical trials and future directions of the new potent combination drug TAS-102.
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PMID:Therapeutic potential of the dual-targeted TAS-102 formulation in the treatment of gastrointestinal malignancies. 1744 63