Therapeutic potential of the dual‐targeted TAS‐102 formulation in the treatment of gastrointestinal malignancies

作者：Olaf H. Temmink, Tomohiro Emura, Michiel de Bruin, Masakazu Fukushima, Godefridus J. Peters · 发表于：Cancer Science · 年份：2007 · DOI：10.1111/j.1349-7006.2007.00477.x · 被引用次数：110 · 研究领域：Colorectal Cancer Treatments and Studies、Gastric Cancer Management and Outcomes、Cancer Treatment and Pharmacology

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 o...