Fluoropyrimidines, oral

T. Ishikawa, M. Utoh, N. Sawada, M. Nishida, Y. Kukase, F. Sekiguchi, H. Ishitsuka, Tumor Selective Delivery of 5-Fluorouracil by Capecitabine, a New Oral Fluoropyrimidine Carbamate, in Human Cancer Xenografts , Biochem. Pharmacol. 1998, JJ, 1091 - 1097. 

The recent availability of oral formulations of 5-FU, may provide not only an improvement in the ease of administration and the efficacy of fluoropyrimidine therapy, but also alleviate complications related to the catheters. Such agents include uracil tegafur (UFT) and capecitabine (Xeloda). 

Budman DR, Meropol NJ, Reigner B, et al. Preliminary studies of a novel oral fluoropyrimidine carbamate capecitabine. J Clin Oncol 1998 16 1795-1802. 

A number of fluoropyrimidines other than 5-FU have been s mthesized, most of which act as prodrugs for 5-FU. Capecitabine (Xeloda ) is an orally administered fluorop5Tim-idine that is converted to 5-FU by the enzyme thymidine phosphorylase (TP), which is often over-expressed in malignant compared to normal tissues (29). Capecitabine has been shown to be equivalent to 5-FU/LV and was the first oral agent to be approved by the FDA for the treatment of mCRC (30). 

Sakata Y, Ohtsu A, Horikoshi N et al. Late phase II study of novel oral fluoropyrimidine antieaneer drug S-1 (1 Mtegafur-0.4M gimestat-1 M otastat potassium) in advaneed gastrie eancer patients. Eur J Cancer 1998 34 1715-1720. 

Fluoropyrimidines (e.g., 5-FU, oral capecitabine) remain unchallenged as reference drugs for treating munerous solid tumors in adults, including digestive, head and neck, and breast cancers. The wide inter-patient variability observed in the pharmacokinetic profiles of these drugs is mainly caused by the erratic activity of dihydropyrimidine... 

Capecitabine is a fluoropyrimidine carbamate prodrug with 70-80% oral bioavailability. It undergoes extensive metabolism in the liver by the enzyme carboxylesterase to an intermediate, 5 -deoxy-5-fluorocytidine. This is converted to 5 -deoxy-5-fluorouridine by the enzyme cytidine deaminase. These two initial steps occur mainly in the liver. The 5 -deoxy-5-fluorouridine metabolite is then hydrolyzed by thymidine phosphorylase to 5-FU directly in the tumor. The expression of thymidine phosphorylase has been shown to be significantly higher in a broad range of solid tumors than in corresponding normal tissue, particularly in breast cancer and colorectal cancer. 

Although not a taxane, ixabepilone is a novel microtubule inhibitor that was recently approved for metastatic breast cancer in combination with the oral fluoropyrimidine capecitabine or as monotherapy. It is a semisynthetic analog of epothilone B, and is active in the M phase of the cell cycle. This agent binds directly to 6-tubulin subunits on microtubules, leading to inhibition of normal microtubule dynamics. Of note, this agent continues to have activity in drug-resistant tumors that overexpress P-glycoprotein or tubulin mutations. The main adverse effects include myelosuppression, hypersensitivity reactions, and neurotoxicity in the form of peripheral sensory neuropathy. 

Capecitabine [cape SITE ah bean] is a novel oral fluoropyrimidine carbamate. It was approved in 1999 for the treatment of metastatic breast cancer that is resistant to first line drugs [for example, pacli-taxel (see p. 391) and anthracyclines], and is currently also used for treatment of colorectal cancer. 

Hoff P (2003) Practical considerations in the use of oral fluoropyrimidines. Seminars in Oncology 30(Suppl 6) 88-92. 

Fluoropyrimidine-based prodrugs A new development are the oral prodrugs ftorafur and capecitabin. Both substances have already proved effective. Capecitabin should not be combined with folinic acid. 

Capecitabine is approved by the FDA for the treatment of (1) metastatic breast cancer in patients who have not responded to a regimen of paclitaxel and an anthracycline antibiotic (2) metastatic breast cancer when used in combination with docetaxel in patients who have had a prior anthracycline-containing regimen and (3) metastatic colorectal cancer for patients in whom fluoropyrimidine monotherapy is preferred. The recommended dose is 2500 mg/m daily, given orally in two divided doses with food, for 2 weeks followed by a rest period of 1 week. This cycle is then repeated two more times. 

Fuchs CSet al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer results from the BICC-C study. Journal of Clinical Oncology 2007 25 4779-4786. 

Capecitabine is a tumor-selective oral fluoropyrimidine. It has been approved by the FDA and NICE for the treatment of colorectal cancer in both the adjuvant and metastatic settings and for patients with breast cancer after anthracycline and taxane therapy [93 ,94 ]. It has also been approved by NICE for advanced gastric cancer as part of platinum-based therapy [95 ]. In a randomized phase III study of adjuvant capecitabine versus fluorouracil -I- leucovorin, efficacy was similar between the groups but grade 3/4 adverse reactions were significantly less common in those who were given capecitabine [96 ]. The starting dose is usually 1000-1250 m m bd for 14 days, followed by 7 days rest. 

Hoff PM, Cassidy J, SchmoU HJ. The evolution of fluoropyrimidine therapy from intravenous to oral. Oncologist 2001 6 (Suppl. 4) 3-11. 

Sulkes A, Benner SE, Canetta RM. Uracil-ftorafur an oral fluoropyrimidine active in colorectal cancer. J Clin Oncol 1998 16(10) 3461-75. 

R. J. Ignoffo, Novel oral fluoropyrimidines in the treatment of metastatic colorectal cancer. Am. ]. Health-Syst. Pharm., 56, 2417-2428 (1999). 

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