s-1-(combination) and eniluracil

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Colonic Neoplasms; Deoxycytidine; Dihydrouracil Dehydrogenase (NADP); Drug Combinations; Enzyme Inhibitors; Fluorouracil; Humans; Oxaloacetates; Oxonic Acid; Tegafur; Uracil

Since its synthesis over 40 years ago, several studies including patients with colorectal cancer have shown that prolonged exposure to 5-fluorouracil (5-FU) is associated with better antitumor activity and decreased toxicity. However, the use of continuous-infusion 5-FU is costly and is associated with the need for a catheter and infusion pump. The use of an oral formulation of 5-FU allows protracted exposure without the inconvenience and cost of intravenous continuous-infusion regimens. Capecitabine is a rationally designed fluoropyrimidine that can be given orally and uses the high concentration of thymidine phosphorylase within cancer cells to concentrate heavily within the tumor. Two large randomized studies that included patients with metastatic colorectal cancer have shown superior response rates for capecitabine compared with bolus regimens of 5-FU with equal times to progression, overall survival, and duration of response. Because of its favorable toxicity profile and the efficacy shown in early trials, capecitabine is currently being investigated in the adjuvant setting and in combination with radiotherapy and with other chemotherapy agents.

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Capecitabine; Clinical Trials as Topic; Colorectal Neoplasms; Deoxycytidine; Drug Combinations; Fluorouracil; Humans; Oxonic Acid; Prodrugs; Pyridines; Tegafur; Uracil

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Drug Combinations; Fluorouracil; Humans; Leucovorin; Oxonic Acid; Pyridines; Tegafur; Uracil

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.

Topics: Administration, Oral; Animals; Antimetabolites, Antineoplastic; Antineoplastic Agents; Breast Neoplasms; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Drug Combinations; Fluorouracil; Humans; Leucovorin; Oxonic Acid; Pyridines; Tegafur; Uracil

Protracted intravenous infusions of fluorouracil (5-FU) in the treatment of colorectal cancer have been associated with a reduction in toxicity and enhanced clinical activity compared with bolus 5-FU schedules. However, these protracted infusions require portable infusion pumps and central venous lines, which are associated with complications of venous thrombosis, infection, and line slippage. An effective oral 5-FU formulation could provide a more convenient protracted treatment method with fewer complications. Because of its inconsistent and erratic absorption, the use of oral 5-FU was abandoned decades ago. The inconsistent absorption of oral 5-FU may be attributed to varying levels of dihydropyrimidine dehydrogenase (DPD) in the gastrointestinal tract. Two methods have been used to circumvent 5-FU's metabolism by DPD in the gastrointestinal tract. First, DPD may be inactivated, allowing for reliable, consistent absorption of 5-FU. Second, 5-FU prodrugs can be administered, being absorbed as intact molecules via the gastrointestinal tract and subsequently converted to 5-FU. The oral fluoropyrimidines discussed here are capable of providing prolonged 5-FU exposure with a reduced incidence of toxicity.

Topics: Animals; Antimetabolites, Antineoplastic; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Dihydrouracil Dehydrogenase (NADP); Drug Combinations; Enzyme Inhibitors; Fluorouracil; Folic Acid Antagonists; Humans; Leucovorin; Oxidoreductases; Oxonic Acid; Prodrugs; Pyridines; Tegafur; Uracil

Although gastric carcinoma is an uncommon disease in North America, its incidence is alarmingly high in Asia, South America, Eastern Europe, and countries of the former Soviet Union. Screening for gastric carcinoma is performed only on a limited basis in Japan; in the rest of the world, therefore, patients often present with advanced disease at the time of diagnosis. Chemotherapy, radiotherapy, or both rarely cure patients with unresectable or metastatic carcinoma; therapy thus remains palliative for such patients. Chemotherapy seems to be beneficial, however, and continues to evolve in the treatment of patients with advanced gastric carcinoma. Four small randomized trials demonstrated survival and quality-of-life benefits for patients who received chemotherapy compared with those who received best supportive care. In the past 20 years, several "old" drugs have been studied either alone or in combination to treat this disease; and new active drugs have been identified. Recently, quality of life, convenience, and cost-containment have been emphasized in the treatment of cancer. This has increased interest in oral agents. At present, several promising oral 5-fluorouracil prodrugs are being studied in clinical trials. This article summarizes current developments in the treatment of advanced gastric carcinoma.

Topics: Administration, Oral; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Camptothecin; Capecitabine; Deoxycytidine; Docetaxel; Drug Combinations; Enzyme Inhibitors; Etoposide; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Oxonic Acid; Paclitaxel; Pyridines; Randomized Controlled Trials as Topic; Stomach Neoplasms; Taxoids; Tegafur; Uracil