Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

After nearly four decades of clinical experience with the fluoropyrimidines, 5-fluorouracil (5-FU) remains an integral part of chemotherapy for colorectal cancer. A range of 5-FU treatment regimens with or without biochemical modulation are currently used and toxicity appears to be schedule dependent. The use of oral 5-FU was abandoned because of erratic absorption caused by varying levels of dihydropyrimidine dehydrogenase (DPD) found in the gastrointestinal tract. This effect may be overcome by administering agents that are converted to 5-FU or by inhibiting or inactivating DPD. Xeloda((R)) (capecitabine) was designed as an orally administered, selectively tumoractivated(TM) cytotoxic agent which achieves higher levels of 5-FU in the primary tumor than in plasma or other tissues. The United States Food and Drug Administration (FDA) has approved Xeloda for use in patients with metastatic breast cancer resistant to paclitaxel and in whom further anthracycline therapy is contraindicated. Xeloda is also registered in Canada, Switzerland, Thailand and Argentina. In phase II clinical trials in colorectal cancer, Xeloda produced response rates of 21-24% and median time to disease progression of 127-230 days. Other oral agents in development for the treatment of colorectal cancer include tegafur/uracil plus oral leucovorin, S-1 and eniluracil plus oral 5-FU.
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PMID:Fluoropyrimidines: a critical evaluation. 1043 10

5-Fluorouracil (5-FU) plays an important role in the treatment of several tumor types, particularly colorectal cancer and breast cancer. Xeloda (capecitabine; 5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl-cytidine]) is a new rationally designed fluoropyrimidine carbamate. It is administrated orally and after absorption it is first metabolized to 5'-deoxy-5-fluorocytidine (5'-DFCR) by carboxylesterase from the liver and then converted to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytidine deaminase from the liver and tumor tissues. Finally, thymidine phosphorylase (TP) converts 5'-DFUR to 5-FU. TP is more active in tumor tissues than in normal tissue. This tissue localization pattern results in preferential metabolism and generates higher levels of 5-FU in malignant tissue, thus enhancing efficacy but minimizing side effects. The tumor tissue selectivity was confirmed in a study of 19 patients with colorectal cancer. After Xeloda administration, concentrations of 5-FU were 2.5 times higher in the primary tumor compared with adjacent healthy tissue. Xeloda was highly active in human tumor xenografts. It was more active than 5-FU, 5'-DFUR and tegafur plus uracil (UFT) and had a better therapeutic index. Xeloda also demonstrated synergistic or additive activity when used in combination with cyclophosphamide, methotrexate, doxorubicin, paclitaxel and docetaxel. This may be in part a result of up-regulation of TP by the cytotoxic agents. Phase I and II clinical trials have shown that Xeloda is active across a range of tumor types, and phase III studies are ongoing.
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PMID:Rational design of new tumoractivated cytotoxic agents. 1043 11