levoleucovorin and eniluracil

The management of patients with metastatic colorectal cancer (CRC) has changed dramatically over the last five years, with increasing chances of prolonged survival. The development of new drugs has contributed to the better outcome of patients with metastatic colorectal cancer. Until the mid-1990s the only available drug, with limited activity in metastatic CRC, was 5-fluorouracil (5-FU). The development of the cytotoxic agents irinotecan, oxaliplatin and capecitabine and of the monoclonal antibodies against the vascular endothelial growth factor (VEGF) bevacizumab and against the epidermal growth factor receptor (EGFR) cetuximab and panitumumab have clearly increased the therapeutic options and have improved the outcome for patients with metastatic colorectal cancer. However, their introduction also raises many new questions and challenges.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Cell Death; Cell Survival; Colorectal Neoplasms; Deoxycytidine; Drug Combinations; ErbB Receptors; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Tegafur; Treatment Outcome; Uracil; Vascular Endothelial Growth Factor A

Either alone or in combination with other antineoplastics, fluorouracil (5-FU) has been the mainstay of treatment of gastrointestinal, breast, and head and neck cancers for the past 40 years. Numerous active 5-FU schedules are in clinical use, but erratic oral bioavailability has historically mandated intravenous administration. Recently, two methods have been used to overcome the poor oral bioavailability of 5-FU. The first involves the use of prodrugs that are absorbed intact in the gastrointestinal tract and are ultimately converted to 5-FU in normal or tumor tissues. An alternate approach involves the inhibition of gastrointestinal degradation via coadministration of an inhibitor of dihydropyrimidine dehydrogenase, the rate-limiting enzyme in 5-FU catabolism. The oral fluoropyrimidines currently in development result in prolonged exposure to 5-FU and, therefore, have the potential to achieve clinical benefits similar to those seen with protracted intravenous infusions of 5-FU, but without the cost, complications, and inconvenience of ambulatory infusion pumps. This review describes several oral fluoropyrimidine regimens with activity in colorectal cancer: capecitabine (Xeloda), tegafur, UFT, S-1, and eniluracil plus 5-FU. An understanding of the distinct mechanisms of action and toxicity patterns of each regimen may ultimately guide treatment selection when multiple choices become available.

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Antineoplastic Agents; Biological Availability; Capecitabine; Colorectal Neoplasms; Decision Making; Deoxycytidine; Enzyme Inhibitors; Fluorouracil; Humans; Leucovorin; Tegafur; Uracil

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

For several years, fluorinated pyrimidines have been used in the treatment of advanced colorectal cancer, mainly in the form of intravenous injections of 5-fluorouracil (5-FU), alone or in combination with leucovorin. Oral treatment with 5-FU has been difficult because of high toxicity and low bioavailability.. Increased knowledge of the metabolism of 5-FU, reviewed in this article, has led to the development of a number of new oral drugs for the treatment of advanced colorectal cancer. Administration of prodrugs and inhibitors of 5-FU-catabolic enzymes has led to stable and high levels of active drug. Several drugs have shown promising results in new clinical trials.. New 5-FU related drugs for oral administration show results comparable to those of the cytotoxic drugs that have been administered in hospital. In the future, general practitioners could possibly treat and follow up a larger proportion of these patients.

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Dihydrouracil Dehydrogenase (NADP); Drug Combinations; Enzyme Inhibitors; Fluorouracil; Humans; Leucovorin; Oxidoreductases; Prodrugs; Pyrimidines; Tegafur; Uracil

Fluorouracil (5-FU) has remained the standard therapy for the treatment of advanced colorectal cancer for over 40 years. Unfortunately, only a minority of patients experience objective clinical response. Discussed herein are attempts to improve on the activity of 5-FU by biochemically modulating its action. In addition, novel agents for the treatment of advanced colorectal cancer (oral fluoropyrimidines, oxaliplatin, and irinotecan) are discussed. Oral fluoropyrimidines (UFT plus leucovorin, capecitabine, eniluracil plus oral 5-FU) provide the convenience of oral delivery with a marked reduction in febrile neutropenia and mucositis. Recent randomized trials with these agents have demonstrated therapeutic activity that is comparable with intravenous schedules of 5-FU plus leucovorin. Compared to 5-FU, both oxaliplatin and irinotecan have uniquely different mechanisms of action and have demonstrated clinical activity in patients whose disease has progressed with 5-FU treatment. Combinations of either irinotecan or oxaliplatin plus 5-FU/leucovorin have demonstrated that the addition of these agents to 5-FU/leucovorin improves response rates and time to progression compared to 5-FU/leucovorin alone. Combination chemotherapy regimens with these novel agents are rapidly being introduced into the adjuvant setting.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Deoxycytidine; Fluorouracil; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Randomized Controlled Trials as Topic; Tegafur; Treatment Outcome; 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

Protracted intravenous regimens of 5-fluorouracil (5-FU) produce fewer toxic effects and greater response rates than do bolus infusion regimens. An effective oral regimen would allow a protracted course of 5-FU without the need for central venous lines and the associated increase in complications, such as venous thrombosis, infection, and line slippage. Dihydropyrimidine dehydrogenase (DPD) is the primary catabolic enzyme of 5-FU. The varying levels of DPD located in the gastrointestinal tract make the absorption of oral 5-FU and resultant plasma levels erratic. The use of 5-FU pro-drugs and/or DPD inhibitors can overcome this absorption problem and allow for oral dosing of fluoropyrimidines. In Japan, oral fluoropyrimidines have been used for decades and have gained widespread acceptance in the treatment of cancer. More recently, encouraging clinical results have led to the development of a new generation of oral fluoropyrimidines, commonly referred to as DPD inhibitory fluoropyrimidines, that specifically target DPD. Several DPD inhibitory fluoropyrimidines are in advanced stages of clinical development in the United States. As studies have shown so far, DPD inhibitory fluoropyrimidine can prolong exposure to 5-FU, while causing fewer toxic effects, and may have therapeutic advantage over intravenous 5-FU.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Dihydrouracil Dehydrogenase (NADP); Enzyme Inhibitors; Fluorouracil; Humans; Leucovorin; Oxidoreductases; Uracil

Topics: Administration, Oral; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Clinical Trials as Topic; Combined Modality Therapy; Deoxycytidine; Female; Floxuridine; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Recurrence, Local; Neoplasms; Tegafur; Time Factors; Uracil

As part of a comparative phase II study of eniluracil/5-FU/Lv vs. capecitabine (Xeloda), an oral 5-FU prodrug for MBC, patients with rapid PD during capecitabine therapy crossed over to take eniluracil/5-FU/Lv.. Ten evaluable patients with radiologically documented PD within 70 days of capecitabine treatment were treated with a modified oral weekly eniluracil/5-FU/Lv regimen.. After switching to eniluracil/5-FU/Lv, 3 (30%) patients had PR. Six (60%) had SD, producing a total of 90% with PR or SD. The median PFS was 140 days (vs. 42.5 days for capecitabine). Four (40%) patients had > 7 months PFS. Eniluracil/5-FU/Lv was well tolerated with mild to moderate diarrhea and nausea as the most common side effects.. These positive efficacy and safety results encourage a larger study in patients with rapid PD during capecitabine treatment. Eniluracil/5-FU/Lv might enable these patients to continue with oral 5-FU rather than switching to the generally less well tolerated intravenous microtubule-interfering agents. In addition, the eniluracil/5-FU/Lv regimen might also provide any overall survival contribution of 5-FU that, for pharmacokinetic reasons, was not provided by capecitabine and would not be provided if these patients progressed directly to the other approved treatments.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Deoxycytidine; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Treatment Failure; Uracil

To determine the toxicities and pharmacokinetic effects of eniluracil (EU) given on two weekly dosing schedules with 5-fluorouracil (5-FU) and leucovorin (LV).. A group of 26 patients received a single 24-h i.v. infusion of 5-FU 2300 mg/m(2) to provide a pharmacokinetic reference. After 2 weeks, patients received oral EU 20 mg plus LV 30 mg on days 1-3 with a single dose of 5-FU 15-29 mg/m(2) on day 2, or LV 30 mg on days 1-2 with a single dose of EU at least 1 h prior to 5-FU 29 mg/m(2) on day 2 weekly for 3 of 4 weeks.. Diarrhea was the most common dose-limiting toxicity. The recommended dose of 5-FU is 29 mg/m(2) per day. EU on either schedule decreased 5-FU plasma clearance by 48 to 52-fold, prolonged the half-life to >5 h, and increased the percentage of 5-FU excreted in the urine from 2% to 64-66%. With EU, plasma fluoro-beta-alanine was not detected while urinary excretion was reduced to <1% of that seen with i.v. 5-FU alone. Marked increases in both plasma and urinary uracil were seen. Thymidylate synthase ternary complex formation was demonstrated in bone marrow mononuclear cells isolated 24 h after the first oral 5-FU dose; the average was 66.5% bound.. Either a single 20-mg dose of EU given prior to or for 3 days around the oral 5-FU dose led to comparable effects on 5-FU pharmacokinetic parameters, and inhibition of dihydropyrimidine dehydrogenase and thymidylate synthase.

Topics: Administration, Oral; Adult; Aged; Antimetabolites, Antineoplastic; Area Under Curve; Enzyme Inhibitors; Female; Fluorouracil; Half-Life; Humans; Infusions, Intravenous; Leucovorin; Male; Metabolic Clearance Rate; Middle Aged; Neoplasms; Uracil

To compare the efficacy and tolerability of eniluracil (EU)/fluorouracil (5-FU) with that of 5-FU/leucovorin (LV) as first-line therapy for patients with metastatic/advanced colorectal cancer.. This multicenter, randomized, open-label, phase III study (FUMA3008) conducted in the United States and Canada compared the safety and efficacy of EU/5-FU (11.5 mg/m(2)/1.15 mg/m(2) twice daily for 28 days every 35 days) with that of intravenous 5-FU/LV (425 mg/m(2)/20 mg/m(2) once daily for 5 days every 28 days) in patients with previously untreated metastatic colorectal cancer. Overall survival (OS) was the primary end point.. A total of 981 patients were randomized and 964 patients received treatment (485 EU/5FU, 479 5FU/LV). Survival for EU/5-FU was not statistically equivalent (but not statistically inferior) to that for 5-FU/LV (hazard ratio, 0.880; 95% confidence interval [CI], 0.75 to 1.03). Median duration of survival was 13.3 months in the EU/5-FU group and 14.5 months in the 5-FU/LV group. Median duration of progression-free survival for EU/5-FU was statistically inferior to that of the control group (20.0 weeks [95% CI, 19.1 to 20.9 weeks] v 22.7 weeks [95% CI, 18.3 to 24.6 weeks]; P =.01). Both treatments were well tolerated. Diarrhea was the most common nonhematologic toxicity in both groups; treatment-related grade 3 or 4 diarrhea occurred in 19% of patients treated with EU/5-FU and 16% of patients receiving 5-FU/LV (P =.354). Grade 3 or 4 granulocytopenia occurred in 5% of EU/5-FU patients and 47% of 5-FU/LV patients.. Safety profiles of both treatments were acceptable. Although antitumor activity was observed, EU/5-FU did not meet the protocol-specified statistical criteria for equivalence to 5-FU/LV in terms of OS.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease Progression; Drug Administration Schedule; Drug Synergism; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Proportional Hazards Models; Survival Analysis; Treatment Outcome; Uracil

This study determined the effect of different weekly dosing schedules of 5-fluorouracil (5-FU)/leucovorin (LV)/eniluracil on dihydropyrimidine dehydrogenase (DPD) activity and plasma uracil levels.. Plasma and mononuclear cells were isolated from peripheral blood samples obtained before, during, and at various times after 5-FU/LV/eniluracil therapy. Two schedules were studied: 20 mg of eniluracil p.o. plus 30 mg of LV p.o. on days 1-3 with a single dose of 5-FU given day 2, or 30 mg of LV p.o. on days 1-2 with a single dose of eniluracil and 5-FU on day 2. DPD activity was determined with a radioisotopic enzyme assay; the reaction products were separated by high-performance liquid chromatography. Plasma uracil levels were determined by gas chromatography-mass spectroscopy.. During oral therapy, DPD activity was profoundly depressed, and uracil levels were strikingly elevated with both schedules. With the daily-for-3-days schedule, DPD activity was similar to baseline values by 3 weeks after the earlier eniluracil dose, whereas it appeared to recover earlier in patients receiving the single-dose schedule, reaching baseline values by 2 weeks. Although baseline uracil values did not predict DPD activity accurately, plasma uracil levels >0.95 microM were associated with significantly lower DPD activity (median, 18.4 versus 287.6 pmol/min/mg).. When eniluracil is given with 5-FU/LV, DPD inhibition appears to be influenced by schedule, and the time to recovery is much longer than has been observed with eniluracil given alone.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dihydrouracil Dehydrogenase (NADP); Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Leukocytes, Mononuclear; Male; Middle Aged; Neoplasms; Oxidoreductases; Time Factors; Uracil

The oral administration of 5-fluorouracil (5-FU) is hindered by erratic bioavailability due to catabolism of 5-FU by the enzyme dihydropyrimidine dehydrogenase (DPD) in the gastrointestinal tract. Eniluracil is a potent inactivator of DPD which results in 100% oral bioavailability of 5-FU. Leucovorin (LV) is another biochemical modulator of 5-FU that potentiates inhibition of thymidylate synthase, the primary target of 5-FU. The goal of this study was to determine the antitumor activity and toxicity of an oral regimen containing eniluracil, 5-FU, and LV in patients with colorectal carcinoma.. Sixty eligible patients who had previously untreated, measurable, metastatic colorectal carcinoma were treated with oral eniluracil 50 mg on Days 1-7, 5-FU 20 mg/m(2) on Days 2-6, and LV 50 mg on Days 2-6. Cycles were repeated at 28-day intervals.. The overall response rate was 13% (95% confidence interval [CI] = 6, 25%), with 1 complete response and 7 partial responses. Three additional patients had partial responses that were not confirmed at subsequent evaluations. The median time to progression of disease was 4.4 months (95% CI = 3.45, 7.69) and the median survival time was 12.6 months (95% CI = 9.1, 14.75). Grade 3-5 toxicity (1 toxic death) occurred in 51 patients (85%). Grade 4 neutropenia occurred in 25 patients (42%), and 18 patients (30%) had Grade 3-4 diarrhea. Twenty-one patients (35%) were hospitalized for toxicity, and 12 (20%) had febrile neutropenia. Baseline creatinine clearance was associated inversely with severe toxicity (P = 0.001).. Although antitumor activity was observed, the frequent occurrence of severe toxicity with this regimen limited its clinical utility. Alternate schedules with a more favorable therapeutic index are undergoing clinical testing and should be pursued. The high level of toxicity observed with orally administered low dose 5-FU underscored the potency of eniluracil as a biochemical modulator.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colorectal Neoplasms; Dihydrouracil Dehydrogenase (NAD+); Disease Progression; Enzyme Inhibitors; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Oxidoreductases; Oxidoreductases Acting on CH-CH Group Donors; Thymidylate Synthase; Uracil

To evaluate the safety and efficacy of a five-day regimen of oral 5-fluorouracil (5-FU) plus eniluracil (776C85) in patients with metastatic colorectal cancer (CRC).. Seventy-five patients with metastatic CRC that was previously untreated or refractory to 5-FU-leucovorin (LV) were enrolled and divided into two strata based upon their treatment history. Twenty-four had not previously received chemotherapy or had received adjuvant chemotherapy that ended > 6 months prior to enrollment on study (previously untreated stratum). Fifty-one patients had disease refractory to intravenous (i.v.) 5-FU-LV (previously treated stratum). All patients received seven consecutive daily doses of eniluracil (20 mg/day) with once daily oral 5-FU given on days 2-6, repeated every four weeks. One-half of the patients in each stratum also received 50 mg/day oral LV on days 2-6. The 5-FU dose was 25 mg/m2 when administered without LV and 20 mg/m2 when administered with LV.. Partial response (PR) was noted in 2 of 12 patients receiving eniluracil-5-FU and in 3 of 12 patients receiving eniluracil-5-FU-LV in the previously untreated stratum. No responses were observed in the refractory disease stratum, however, 15 patients (30%) demonstrated stable disease over 2-18+ courses of therapy. Non-hematologic toxicities were mild; only 7% of patients experienced grade 3 diarrhea. Myelosuppression was frequent and dose limiting. Neutropenic sepsis was reported in 13.5% of patients.. Eniluracil with 5-FU administered orally with or without LV on a five-day schedule is active and well tolerated when given as primary therapy to patients with metastatic CRC.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Combined Modality Therapy; Disease-Free Survival; Drug Administration Schedule; Enzyme Inhibitors; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Treatment Outcome; Uracil

Fluorouracil (5-FU) given as a weekly, high-dose 24-hour infusion is active and tolerable. We evaluated an oral regimen of eniluracil (which inactivates dihydropyrimidine dehydrogenase [DPD]), 5-FU, and leucovorin to simulate this schedule.. Patients received a single 24-hour infusion of 5-FU (2,300 mg/m(2) on day 2) with leucovorin (15 mg orally [PO] bid on days 1 through 3) to provide reference pharmacokinetic data. Two weeks later, patients began treatment with eniluracil (20 mg) and leucovorin (15 mg) (PO bid on days 1 through 3) and 5-FU (10 to 15 mg/m(2) PO bid on day 2).. Dose-limiting toxicity (diarrhea, neutropenia, and fatigue) was seen with 5-FU 15 mg/m(2) PO bid on day 2 given weekly for either 6 of 8 weeks or 3 of 4 weeks, whereas five of seven patients tolerated 5-FU 10 mg/m(2) PO bid given weekly for 3 of 4 weeks. Eniluracil led to a 35-fold reduction in 5-FU clearance. Fluoro-beta-alanine, a 5-FU catabolite, was not detected in plasma during oral 5-FU-eniluracil therapy. DPD activity was markedly suppressed in all patients during eniluracil therapy; the inactivation persisted after the last eniluracil dose; percentages of baseline values were 1.8% on day 5, 4.5% on day 12, and 23.6% on day 19.. The recommended oral dosage of 5-FU (10 mg/m(2) PO bid) given with eniluracil and leucovorin is approximately 115-fold lower than the reference dosage for 24-hour infusional 5-FU. This difference is greater than expected given the reduction in 5-FU clearance. DPD inactivation persisted for several weeks after completion of eniluracil therapy.

Topics: Administration, Oral; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Dihydrouracil Dehydrogenase (NADP); Drug Administration Schedule; Enzyme Inhibitors; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasms; Oxidoreductases; Uracil

To determine the highest dose of fluorouracil (5-FU) that could be safely administered with Eniluracil (776C85; Glaxo Wellcome Inc, Research Triangle Park, NC), an inactivator of dihydropyrimidine dehydrogenase (DPD), on a daily schedule for 5 days, and to define the toxicities of the combination and the pharmacokinetics of 5-FU when administered with 776C85.. Patients with advanced solid tumors refractory to standard therapy were enrolled at two institutions. The study consisted of three periods designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of 776C85 alone (period 1); the effects of 776C85 on the pharmacokinetics of 5-FU (period 2); and the maximum-tolerated dose (MTD) of 5-FU, with or without leucovorin, that could be safely administered with 776C85 (period 3). Cohorts of at least three patients each received oral 776C85 alone at doses of 3.7 mg/m2/d, 18.5 mg/m2/d and 0.74 mg/m2/d. After a 14-day washout period, each patient then received 776C85 daily for 3 days, with a single intravenous (i.v.) bolus dose of 5-FU 10 mg/m2 on day 2. After a second washout period, patients were treated with 776C85 daily for 7 days and 5-FU i.v. bolus on days 2 through 6. The starting dose of 5-FU 10 mg/m2/d was escalated until the MTD was determined. After determination of the MTD of 5-FU given with 776C85, oral leucovorin 50 mg/d on days 2 through 6 was added to determine the MTD of 5-FU with leucovorin in the presence of 776C85. Near the completion of the study, additional cohorts of patients were treated with 776C85 at 50 mg/d and oral 5-FU with or without leucovorin.. Sixty-five patients were enrolled onto the study and 60 were assessable for toxicity and response. Bone marrow suppression was the primary and dose-limiting toxicity of this regimen. Other toxicities included diarrhea, mucositis, anemia, anorexia, nausea, vomiting, and fatigue. 776C85 suppressed DPD activity in peripheral-blood mononuclear cells (PBMCs) by at least 90% for at least 24 hours at all dose levels tested. In the presence of 776C85, 5-FU half-life was prolonged, clearance was reduced, and the drug displayed linear pharmacokinetics. Recommended doses for further testing on a daily for 5-day schedule are 776C85 10 mg/d with i.v. 5-FU 25 mg/m2/d; 776C85 10 mg/d with i.v. 5-FU 20 mg/m2/d plus leucovorin 50 mg/d; 776C85 50 mg/d with 5-FU given orally at 15 mg/m2/d with leucovorin at 50 mg/d.. 5-FU can be safely administered with 776C85; however, the MTDs are considerably lower than those conventionally used, caused, at least in part, by marked alterations in 5-FU plasma pharmacokinetics.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Dihydrouracil Dehydrogenase (NADP); Drug Interactions; Enzyme Inhibitors; Female; Fluorouracil; Gas Chromatography-Mass Spectrometry; Half-Life; Humans; Leucovorin; Male; Middle Aged; Neoplasms; Oxidoreductases; Uracil

5-Fluorouracil (5-FU)-associated neurotoxicity is uncommon; symptoms may occur abruptly or more gradually during the course of chemotherapy. Peripheral neuropathy with 5-FU therapy has only rarely been reported. Two patients treated in a phase I trial of oral 5-FU, leucovorin and eniluracil, an inhibitor of dihydropyrimidine dehydrogenase (DPD), developed delayed onset symptoms of unsteady gait and reduced sensation in the legs. Magnetic resonance imaging scans of the brain and neurologic examination did not support a CNS basis for the condition. Electromyograms and nerve conduction studies revealed sensorimotor polyneuropathy. Other common etiologies of peripheral neuropathy were excluded. The neurological condition of these patients stabilized after 5-FU dose reduction and partial resolution gradually occurred when protocol therapy was stopped. Although CNS symptoms may rarely complicate 5-FU therapy, peripheral neuropathy is unexpected. Patients with DPD deficiency treated with conventional doses of 5-FU typically develop acute CNS toxicity shortly after therapy, accompanied by extremely high systemic exposure to 5-FU. Patients with normal 5-FU clearance may also experience CNS toxicity, particularly with high-dose schedules, and both parent drug and its catabolites may be contributory. Since DPD was profoundly inhibited during eniluracil therapy in these two patients, it is likely that 5-FU or its active metabolites were contributing factors to the peripheral neuropathy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain; Colonic Neoplasms; Dihydrouracil Dehydrogenase (NADP); Electromyography; Female; Fluorouracil; Humans; Leucovorin; Magnetic Resonance Imaging; Male; Middle Aged; Oxidoreductases; Peripheral Nervous System Diseases; Time Factors; Uracil

Dihydropyrimidine dehydrogenase (DPD) is the key enzyme of the fluorouracil (FU) catabolic pathway. We have shown that tumor cells expressing a high DPD activity are resistant to FU (Eur J Cancer 30: 1517, 1994), and that 5-ethynyluracil (776C), a very potent DPD inactivator, markedly enhances the FU cytotoxic effect (Clin Cancer Res 1: 991, 1995). Both experimental background and clinical experience have demonstrated the role of folinic acid (FA) in increasing FU efficacy. The aim of the present study was to investigate the dual FU pharmacomodulation based on the combination of FU with 776C and/or FA on 7 human cancer cell lines (2 head and neck, 3 breast, 1 colon, 1 duodenum) expressing a spontaneous FU sensitivity. These cell lines were chosen according to their ability to respond to FU modulation by FA and/or 776C. The potency of FU modulation was evaluated by the ratio between FU IC50 and FU IC50 in the presence of the tested biomodulator(s), defined as factor F. In cell lines sensitive to FU modulation by 776C only (median F value with 1 microM of 776C = 2.5), the addition of FA did not enhance FU-776C cytotoxicity. In contrast, for cell lines resistant to FU modulation by 776C, the FU-FA-776C combination led to a significant cytotoxicity enhancement as compared to FU-FA (median F values were 3.6 and 2.6 respectively). In cell lines responsive to FU modulation by FA and 776C, the median F values were 2.3 and 1.8 with FA and 776C, respectively. Interestingly, the dual modulation by FA + 776C led to a median F value at 6.3, suggesting more than the additive effects of FA and 776C. This synergistic interaction was statistically confirmed by multivariate ANOVA (FA x 776C interaction). The present study points out that FA plus 776C could prove to be a very attractive combination for future strategies in FU biomodulation.

Topics: Cell Survival; Dihydrouracil Dehydrogenase (NADP); Drug Interactions; Drug Synergism; Enzyme Inhibitors; Fluorouracil; Humans; Leucovorin; Oxidoreductases; Thymidylate Synthase; Tumor Cells, Cultured; Uracil

5-Ethynyluracil (EU; 776C85) is a potent inactivator of dihydropyrimidine dehydrogenase, the enzyme that rapidly degrades 5-fluorouracil (FUra). We have investigated the antitumor activity and toxicity of FUra alone and in combination with EU in rats bearing advanced colon carcinoma. Two schedules were studied: (a) FUra daily for 4 days i.v. push (daily x 4); and (b) FUra administered i.v. push weekly for 3 weeks (weekly x 3). EU was administered at 1 mg/kg 1 h before FUra and for two additional days post-FUra therapy. The maximum tolerated doses of FUra alone were 35 and 100 mg/kg/day and for FUra plus EU were 10 and 15 mg/kg/day for the daily x 4 and weekly x 3 schedules, respectively. The dose-limiting toxicities were diarrhea and stomatitis both for FUra alone and for FUra in combination with EU. Although EU was not toxic and not active as an antitumor agent, it markedly improved the efficacy and therapeutic index of FUra. The antitumor activity of FUra was schedule dependent, yielding 13% complete and sustained tumor regression on the weekly schedule and no complete and sustained tumor regression on the daily schedule. The combination of FUra and EU produced 100% complete and sustained tumor regression on both schedules. The therapeutic index was < or = 1 for FUra alone and 6 for FUra with EU. EU was considerably more effective than either leucovorin or N-(phosphonacetyl)-L-aspartate as a modulator of FUra. Leucovorin or N-(phosphonacetyl)-L-aspartate induced minimum improvements on the daily schedule and only increased the therapeutic index to 1.5 on the weekly schedule. Because a 4-day continuous infusion of FUra alone at the maximum tolerated dose did not improve FUra therapy, we conclude that the improvements by EU involve additional modulations that complement the enhanced exposure of FUra.

Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Aspartic Acid; Colorectal Neoplasms; Drug Synergism; Female; Fluorouracil; Leucovorin; Neoplasm Transplantation; Phosphonoacetic Acid; Rats; Rats, Inbred F344; Uracil