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Introduction: Doxifluridine (DF), an oral 5-FU prodrug, has been used for various solid cancers due to its efficacy and low toxicity. We aim to evaluate the effect of DF as adjuvant monotherapy in advanced gastric cancer. Methods: We retrospectively reviewed the clinical data of 263 patients with advanced gastric cancer who underwent curative gastrectomy between January 2010 and December 2013 at our institute. Since previous randomized control trials have confirmed the efficacy of S-1 as adjuvant chemotherapy in advanced gastric cancer, we analyzed the oncologic effect and patient compliance of the DF group compared to the S-1 group. After propensity score matching, 48 patients were included in each group. Results: There was no significant difference in 5-year overall survival (OS) and 5-year disease-free survival (DFS) between DF and S-1 groups (5-year OS; 77.1% vs 75.0%; p = 0.729, 5-year DFS; 76.6% vs 73.9%; p = 0.748). The completion rates of the DF and S-1 groups were 60.4% and 72.9%, respectively (p = 0.194). The mean relative dose intensity of the DF and S-1 groups were 76.2% and 84.2%, respectively (p = 0.195). After multivariate analysis, the chemotherapy regimen was not a risk factor for OS and DFS, whereas relative dose intensity and pathologic stage were independent prognostic factors. Conclusion: There was no significant difference in the oncologic effect and patient compliance between DF and S-1 groups. DF could be an alternative option for adjuvant chemotherapy in advanced gastric cancer. In addition, we confirmed that relative dose intensity is an important independent prognostic factor for survival.

Doxifluridine (DF), an oral 5-FU prodrug, has been used for various solid cancers due to its efficacy and low toxicity. We aim to evaluate the effect of DF as adjuvant monotherapy in advanced gastric cancer. We retrospectively reviewed the clinical data of 263 patients with advanced gastric cancer who underwent curative gastrectomy between January 2010 and December 2013 at our institute. Since previous randomized control trials have confirmed the efficacy of S-1 as adjuvant chemotherapy in advanced gastric cancer, we analyzed the oncologic effect and patient compliance of the DF group compared to the S-1 group. After propensity score matching, 48 patients were included in each group. There was no significant difference in 5-year overall survival (OS) and 5-year disease-free survival (DFS) between DF and S-1 groups (5-year OS; 77.1% vs 75.0%; p = 0.729, 5-year DFS; 76.6% vs 73.9%; p = 0.748). The completion rates of the DF and S-1 groups were 60.4% and 72.9%, respectively (p = 0.194). The mean relative dose intensity of the DF and S-1 groups were 76.2% and 84.2%, respectively (p = 0.195). After multivariate analysis, the chemotherapy regimen was not a risk factor for OS and DFS, whereas relative dose intensity and pathologic stage were independent prognostic factors. There was no significant difference in the oncologic effect and patient compliance between DF and S-1 groups. DF could be an alternative option for adjuvant chemotherapy in advanced gastric cancer. In addition, we confirmed that relative dose intensity is an important independent prognostic factor for survival. [ABSTRACT FROM AUTHOR]

Portal vein tumor thrombosis (PVTT) with advanced gastric cancer is very rare; when it occurs, it exhibits aggressive growth and carries a poor prognosis. In addition, definitive treatment has not been established due to insufficient data. Herein, we report a case of PVTT associated with an adenocarcinoma of the esophagogastric junction that was successfully controlled by means of a palliative total gastrectomy without surgical resection of the PVTT and administration of palliative continuous doxifluridine.

RNase L is activated by 2′,5′-oligoadenylates (2-5A) at subnanomolar levels to cleave single-stranded RNA. We previously reported the hypothesis that the introduction of an 8-methyladenosine residue at the 2′-terminus of the 2-5A tetramer shifts the 2-5A binding site of RNase L. In this study, we synthesized various 5′-modified 2-5A analogs with 8-methyladenosine at the 2′-terminus. The doxifluridine-conjugated 8-methyladenosine-substituted 2-5A analog was significantly more effective as an activator of RNase L than the parent 5′-monophophorylated 2-5A tetramer and showed a tumor suppressive effect against human cervical cancer cells. [ABSTRACT FROM AUTHOR]

Purpose: To improve the efficacy of adjuvant chemotherapy with mitomycin-C and fluoropyrimidine (Mf) in gastric cancer, we designed a new regimen (iceMFP) and investigated in a phase III study. Methods: We randomly assigned 640 patients with resectable and macroscopically recognizable serosa-invading gastric cancer to Mf or iceMFP group during operation. The Mf consisted of intravenous mitomycin-C (20 mg/m) at 3-6 weeks after surgery and oral doxifluridine (460-600 mg/m/day) starting 4 weeks after the administration of mitomycin-C and continuing for 3 months. The iceMFP consisted of intraoperative intraperitoneal cisplatin (100 mg), intravenous mitomycin-C (15 mg/m) on postoperative day 1, followed by oral doxifluridine for 12 months, and six monthly intravenous cisplatin (60 mg/m). The primary endpoint was 3-year recurrence-free survival (RFS). Results: A total of 521 patients (258 in Mf, 263 in iceMFP) were eligible for analysis after excluding patients with stage I disease, distant metastasis, or R1 resection. With a median follow-up of 3.5 years, the iceMFP group had a higher RFS (hazard ratio [HR] 0.70; 95 % confidence interval [CI] 0.54-0.90; p = 0.006; 3-year RFS 60 % vs. 50 %) and overall survival (HR 0.71; 95 % CI 0.53-0.95; p = 0.02; 3-year overall survival, 71 vs. 60 %) compared with the Mf group. This was confirmed at extension analysis after a median 6.6 years of follow-up. Both regimens were well tolerated with no differences in surgical complications. Conclusion: The efficacy of adjuvant Mf was significantly improved by the additional therapeutic strategies of iceMFP. Considering negative results of AMC0201, these suggest that early initiation of chemotherapy and/or intraperitoneal cisplatin played a distinct role in the improved efficacy. [ABSTRACT FROM AUTHOR]

Doxifluridine (5′-deoxy-5-fluorouridine, 5′-dFUR) is a fluoropyrimidine derivative that is activated preferentially in malignant cells by thymidine phosphorylase to form 5-fluorouracil (5-FU). The purpose of this study was to investigate the pharmacokinetic properties of doxifluridine and its two major metabolites, 5-FU, and 5-fluorouridine (5-FUrd), in beagle dogs following a single oral administration of 200 mg doxifluridine capsule (Furtulon ®). After the administration of 200 mg of Furtulon to 23 beagle dogs, the plasma concentrations of doxifluridine, 5-FU, and 5-FUrd were measured simultaneously, using LC–MS/MS. The parent–metabolite compartment model with first-order absorption and Michaelis–Menten kinetics described the pharmacokinetics of doxifluridine, 5-FU, and 5-FUrd. Michaelis–Menten kinetics sufficiently explained the generation and elimination processes of 5-FU and 5-FUrd. The studies described here are the first to evaluate the relationship between pharmacokinetics of doxifluridine and its metabolites in dogs, and these findings will help in understanding the toxicity mechanism of doxifluridine. [ABSTRACT FROM AUTHOR]

Microsatellite instability (MSI) is a molecular marker that can provide valuable prognostic information for colorectal cancer (CRC). However, the predictive role of the MSI status remains less clear than its role in prognostication due to mixed results from previous studies. Therefore, this study investigated the usefulness of the MSI status as a predictive factor for stage II or III CRC patients who received adjuvant doxifluridine therapy. Among 3030 patients with CRC who underwent surgical resection between 1997 and 2006, 564 patients were diagnosed with stage II or III, and adjuvant doxifluridine therapy was administered to 394 patients (70.0%). The MSI status was assessed using the markers BAT25 and BAT26, and samples with instability at both markers were scored as exhibiting high-frequency MSI (MSI-H). Among the 564 patients, 290 patients (51.4%) had stage II, and MSI-H was found in 41 patients (7.3%). With a median follow-up duration of 35.1 months (range, 0.5-135.2), the 5-year overall survival (OS) rate and relapse-free survival (RFS) rate were 87.5 and 76.2%, respectively. MSI-H showed a favorable survival trend for OS ( P = 0.098) and significant survival benefit for RFS ( P = 0.037) in all patients. In a univariate analysis, the doxifluridine-treated patients with MSI-H showed improved RFS compared to those with low or stable MSI (MSI-L/S) ( P = 0.036), while the MSI status was not significantly associated with OS ( P = 0.107). In a multivariate analysis, MSI-H was not significantly associated with RFS (Hazard ratio = 2.467, P = 0.125). In conclusion, this study confirmed the positive prognostic role of MSI-H. However, MSI-H patients with stage II or III CRC did not seem to benefit from doxifluridine adjuvant therapy. [ABSTRACT FROM AUTHOR]

Purpose: There is no standard second-line treatment for patients with unresectable advanced or recurrent gastric cancer (URGC) in the event that first-line treatment fails. Moreover, the benefits of second-line chemotherapy in elderly patients remain uncertain. The aim of this study was to identify the benefits of the second-line paclitaxel (PTX) plus doxifluridine (5′-DFUR) regimen for URGC in elderly patients in comparison to nonelderly patients. Methods: We retrospectively examined the clinical outcomes of the second-line PTX plus 5′-DFUR regimen in patients with URGC, who had previously been treated with S-1-based first-line chemotherapy. Results: A total of 27 patients (10 elderly, ≥70 years old; 17 nonelderly, <70 years old) were enrolled in the study. The clinical benefit rate (complete response, partial response, and stable disease) in the elderly group was 6 of 10 (60%), and that of the nonelderly group was 9 of 17 (53%). Age had no statistically significant influence on the response rate, and no grade 4 adverse events were observed in either group. In addition, the median survival time was 12.2 months in both groups. Conclusion: Although it remains unclear whether second-line chemotherapy contributes to survival in patients with URGC, the combination of PTX plus 5′-DFUR might be the treatment of choice for second-line chemotherapy in both elderly and nonelderly patients who have already received an S-1-based first-line treatment. [ABSTRACT FROM AUTHOR]

Abstract: Several strategies for overcoming the challenge of establishing bioequivalence (BE) for highly variable drugs (HVDs; drugs having within-subject variability >0.3) have been considered in recent years. Within-subject variability of the area under the curve (AUC4h) and peak concentration (C max) of doxifluridine in the minimal group (n =24) were 0.444 and 0.491, respectively, meeting the criteria for an HVD. For the large group (n =60), within-subject variability of the AUC4h and C max were 0.431 and 0.493, respectively. The 90% confidence interval for the AUC4h and C max of the ratio of the test drug to the reference drug exceeded the acceptable BE limits (0.80–1.25) of the ABE (average bioequivalence), in both the minimal and large groups. However, the 90% CI fell within the extended BE limits (0.61–1.64) of the SABE (scaled average bioequivalence), calculated using within-subject variability. The 95% CI of the AUC4h and C max of the ratio of test to reference drug were within the extended BE limit (<1.73) of the PBE (population bioequivalence), calculated using total variance. Our results suggest that the SABE method may be useful for evaluating the BE of HVDs and for meeting the need for international guidelines for BE. [Copyright &y& Elsevier]

The aim of this study was to establish the efficacy and safety of doxifluridine and docetaxel for patients with advanced or recurrent gastric cancer. The regimen consisted of oral administration of doxifluridine 533 mg/m2 per day on days 1–14 and an intravenous infusion of docetaxel 50 mg/m2 on day 8. The primary endpoint was the overall response rate. The secondary endpoints were overall survival, progression-free survival, and toxicities. Between June 2004 and December 2006, a total of 40 eligible patients were enrolled in this study. Seven of them showed a partial response, with an overall response rate of 17.5%. The response rate was 18.8% in 32 patients with refractory tumors. The median progression-free survival time and the median overall survival time were 2.6 months and 12.7 months, respectively, in all 40 patients; and 2.6 months and 14.0 months, respectively, in the 32 patients with refractory tumors. Grade 3/4 hematological toxicity included neutropenia in 52.5%, leukocytopenia in 17.5%, and febrile neutropenia in 7.5%. Grade 3 or more nonhematological toxicities were infrequent. The combination chemotherapy of doxifluridine and docetaxel was well tolerated and relatively effective when used as a second-line chemotherapy for advanced or recurrent gastric cancer. [ABSTRACT FROM AUTHOR]

Abstract: A reverse-phase high performance liquid chromatography method with electrospray ionization and detection by mass spectrometry is described for the simultaneous determination of doxifluridine and its active metabolite 5-fluorouracil in monkey serum. A liquid/liquid extraction with ethyl acetate (90%) and isopropyl alcohol (10%) was used to extract simultaneously doxifluridine and 5-FU which have considerable difference in the polarity. Optimum chromatographic separation was achieved on a Agilent Zorbax C18 (100mm×2.1mm, 3.5μm) column with a mobile phase of methanol–water (20:80, v/v). The flow rate was 0.2mL/min with total cycle time of 5min. The lower limit of quantification (LLOQ) was validated at 10.0ng/mL of serum for both doxifluridine and 5-FU. Accuracy and precision of quality control (QC) samples for both compounds met FDA Guidance criteria of ±15% with average QC accuracy of 95.5–105.0% and coefficients of variation of 1.1–9.5% in the 10–2000ng/mL concentration range. This method demonstrated adequate sensitivity, specificity, accuracy, precision, stability to support the analysis of monkey serum samples. [Copyright &y& Elsevier]

The purpose of this study was to examine the efficacy of a combination treatment of sequential irinotecan and doxifluridine, an intermediate of capecitabine, evaluated by the response rate and safety in patients with metastatic colorectal cancer. In all, 60 metastatic colorectal cancer patients with measurable disease were enrolled. The schedule of the treatment consisted of a 90 min intravenous (IV) infusion of irinotecan 150 mg/m2 for on days 1 and 15, and 600–1,000 mg/body of oral doxifluridine on days 3–14 and 17–28. Cycles were repeated every 35 days. A median of three cycles of the combination therapy (range 1–14 cycles) was administered. A total of 57 patients (95%) completed at least two cycles of the therapy without any dose reductions. There was one complete response and 23 partial responses with an overall response rate of 40% [95% confidence interval (CI): 28–53%]. A total of 19 patients had stable disease, 43(72%) achieved disease control. The median time to progression was 5.9 months and the median overall survival was 20.5 months. Ten (17%) and 17 (28%) patients developed Grade 3–4 leukopenia and neutropenia, respectively. Grade 3–4 fatigue was observed in 7(12%) patients, nausea in five (8%), vomiting in four (7%), and diarrhea,in three (5%) patients. No treatment-related deaths were noted during the study. From these results, the combination of sequential irinotecan and doxifluridine is considered to be an effective, easy-to-administer regimen with acceptable tolerability. [ABSTRACT FROM AUTHOR]

The standard beneficial chemotherapy proven for patients with advanced pancreatic cancer is a regimen containing gemcitabine. In the pregemcitabine era, 5-fluorouracil (5-FU) was the standard agent. Oral 5-FU can be added to gemcitabine to improve the efficacy of chemotherapy and to provide better patient convenience. The possibility to improve efficacy of gemcitabine by fixed dose rate infusion (FDRI) was proposed in addition to combining it with 5-FU. We tried a new chemotherapy combining FDRI of gemcitabine with doxifluridine and leucovorin. Eligibility criteria were pathologically proven, chemotherapy-naïve, and metastatic or nonoperable advanced pancreatic cancer. Gemcitabine 1,000 mg/m2 was infused over 100 min (days 1, 8 and 15). Doxifluridine 200 mg/m2 t.i.d. and leucovorin 15 mg b.i.d. were given orally (days 1–21). Chemotherapy was repeated every 28 days until a patient had received 6 cycles or progression was found. Twenty-nine patients were enrolled from October 2002 to December 2004. A total of 78 cycles were given at a mean of 2.7 cycles per patient. Response could be evaluated in 26 patients. Responses were partial remission in 4/26 patients (15.4%), stable disease in 8/26 (30.8%) and progression in 14/26 (53.8%). All patients progressed except for 2 in partial remission and 2 in stable disease. Toxicities could be assessed in 23 patients. Maximal hematological toxicities greater than grade 2 were leucopenia in 3 patients (11.5%), neutropenia in 2 (7.7%), anemia in 2 (7.7%), thrombocytopenia in 1 (3.8%) and febrile neutropenia in 3 (11.5%). Maximal nonhematological grade 3 or 4 toxicities were asthenia in 1 patient (3.8%), anorexia in 1 (3.8%), vomiting in 1 (3.8%), diarrhea in 2 (7.7%), allergic reaction in 1 (3.8%), hand-foot syndrome in 1 (3.8%) and hyperbilirubinemia in 1 (3.8%). All 29 patients were dead on last follow-up. Median progression-free survival was 3.91 months in 26 evaluable patients and median overall survival was 5.59 months in all patients. Combination chemotherapy including FDRI of gemcitabine seems minimally active for patients with advanced, nonoperable pancreatic cancer. Further research to improve effectiveness of chemotherapy for advanced pancreatic cancer is mandatory. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Advanced prostate cancer, which is one of the most common cancers, usually progresses to hormone-refractory prostate cancer (HRPC). A recent randomized trial of treatment with docetaxel demonstrated improved survival for patients with HRPC. The combination of docetaxel and estramustine phosphate (estramustine) has been reported to be effective for HRPC. Low-dose estramustine suppresses the pituitary–gonadal axis. Docetaxel plus 5-fluoro-5′-deoxyuridine (5′-dFUrd) had supra-additive cytotoxic effects on HRPC cells consistent with the molecular mechanism. Therefore, we examined the efficacy of adding 5′-dFUrd on the chemotherapy regimen, which consist docetaxel and estramustine. All of the HRPC patients were treated with estramustine 140 mg orally twice 5′-dFUrd 200 mg orally four times daily on days 1–21, and docetaxel 60 mg/m2 was administered on day 1. We evaluated serum prostate-specific antigen (PSA) and measurable responses, the progression-free and overall survival, and the impact on adverse effects and the quality of life (QOL). Of 34 patients with a median age of 72.3 years, 73% showed PSA responses and 70% showed measurable responses. The median progression-free survival was 18.0 and 5.8 months for PSA responders and non-responders and the overall survival was 19.4 months, respectively. There were few serious adverse effects. Grade 3/4 neutropenia occurred in 32.4% of the patients, and was easily managed with granulocyte colony-stimulating factor (G-CSF) injection. There was no significant change in the overall QOL scores serially. This study shows that the combined regimen is tolerable and effective in Japanese HRPC patients. [ABSTRACT FROM AUTHOR]

Many patients with gastric cancer respond to TS-1, but some fail to respond or have recurrence. Second-line therapy is needed. We performed a pilot study in patients with advanced gastric cancer who did not respond to TS-1 or who had disease recurrence. The patients received oral doxifluridine (600 mg/day) on days 1 to 21 and an intravenous infusion of paclitaxel (70 mg/m2) on days 7, 14, and 21 of a 28-day cycle. The treatment was repeated until disease progression or prohibitive toxicity. Response rate, duration of response, median survival time (MST), effects on pleural effusion, ascites, and other signs, and toxicity were evaluated. The study group comprised 52 patients. The response rate was 28%. The duration of response was 103 days. The MST after the start of second-line treatment was 175 days (95% confidence interval, 135 to 224 days). Pleural effusion or ascites resolved or decreased in 73% of the patients. Hair loss occurred in 32 patients (62%), and leukopenia developed in 28 (54%, grade 3 in 1 patient and grade 2 or lower in the others). The MST after the start of treatment with TS-1 was about 16 months. A combination of doxifluridine and weekly paclitaxel is expected to be an effective second-line treatment for gastric cancer not responding to TS-1, especially in patients with malignant ascites or pleural effusion. However, it remains unclear whether paclitaxel plus doxifluridine results in a better response and survival benefit than paclitaxel alone in this subgroup of patients. Further studies are therefore necessary. [ABSTRACT FROM AUTHOR]

We report a 72-year-old man who was diagnosed by gastroscopy as having a type III poorly differentiated adenocarcinoma in the lesser curvature, with the longest diameter being 10 cm. An abdominal computed tomography (CT) scan revealed multiple liver metastases, thickening of the gastric wall, and an enlarged paraaortic lymph node. The serum carcinoembryonic antigen (CEA) level was 60 ng/ml and the carbohydrate antigen (CA) 19–9 level was 1355 U/ml. The patient received combined chemotherapy with doxifluridine (800 mg/body per day) and paclitaxel (one course comprised three weekly infusions at a dose of 70 mg/m2 followed by 1-week rest). After the completion of three courses, the patient achieved a complete response (CR), with complete disappearance of the primary tumor, the metastatic foci in the liver, and the enlarged abdominal lymph nodes; as well, the tumor markers were normalized. Adverse effects included only mild anorexia that was limited to grade 1. He maintained a CR for 1 year and 2 months. Combination chemotherapy with paclitaxel and doxifluridine can be an effective treatment for unresectable advanced gastric carcinoma. [ABSTRACT FROM AUTHOR]

Purpose: Anti-tumor activity can often be enhanced with combination therapy in managing patients with metastatic cancer. However, dose sequence and schedule of delivery can alter the pharmacokinetics, toxicity, and anti-tumor response. Therefore, attention to drug-drug interactions which may be sequence or schedule-dependent are necessary. Docetaxel and topotecan are non-cross-resistance cytotoxic agents with activity in a variety of malignancies. The goal of this study was to determine the maximum tolerated dose of docetaxel and continuous infusion topotecan using two sequences of administration. Experimental design: Patients were randomized to schedule A or B and enrolled in four escalating-dose cohorts. On schedule A, docetaxel was administered over 1 h and followed by topotecan administered over 72 h. On schedule B, topotecan was given as a 72 h continuous infusion followed by a 1 h infusion of docetaxel. While the doses for the docetaxel and topotecan were the same for schedule A and schedule B, the toxicities, and thus the determination of maximum tolerated dose (MTD), were assessed independently. The plasma pharmacokinetic disposition of topotecan and docetaxel were evaluated during the first cycle of each sequence to assess drug interactions. Results: Thirty patients, 20 males and 10 females were evaluable for toxicity and response. Four patients were chemonaive. Mean number cycles given were 3. Grade 3/4 thrombocytopenia and neutropenia were comparable on both schedules, as was the dose-limiting toxicity (DLT) for both schedules. There were no apparent differences in absolute neutrophil count or platelet nadirs between schedules A and B for three of the four cohorts. The principal non-hematologic toxicity was nausea and vomiting. The time of overlap of topotecan lactone or total concentrations and docetaxel concentrations were greater on schedule A as compared with schedule B and was associated with reduced clearance of docetaxel on schedule A as compared to schedule B. However, the mean clearance for docetaxel (18∀16 L h-1 m-2 and 29∀28 L h-1 m-2 on schedules A and B, respectively, and topotecan 16∀10 L h-1 m-2 and 7∀6 L h-1 m-2 on schedules A and B, respectively) were not statistically different (P>0.05). Conclusions: The observed toxicity was not sequence-dependent, despite the observed change in kinetics. Docetaxel and topotecan can be administered with acceptable toxicity at the recommended phase-II dose of docetaxel 60 mg m-2 and topotecan 0.85 mg m-2 day-1×3 days. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this study was to compare the efficacy and toxicity of gemcitabine-based concurrent chemoradiotherapy (CCRT) with paclitaxel-based CCRT in patients with locally advanced pancreatic cancer. Methods and materials: A total of 48 patients who had received no prior therapy were enrolled. The patients were treated with 4500 cGy radiation in 25 fractions over 5 weeks concomitant with gemcitabine 1000 mg/m2/week/intravenously (IV) and doxifluridine 600 mg/m2/day/by mouth (PO), or paclitaxel 50 mg/m2/week/IV and doxifluridine 600 mg/m2/day/PO. After a 4-week rest, the responses were evaluated and maintenance therapies (operation or chemotherapy) (gemcitabine 1000 mg/m2/week/IV and doxifluridine 600 mg/m2/day/PO) were conducted. Results: The median survival was 12 months in the gemcitabine group vs. 14 months in the paclitaxel group. The response rate was 13.6% vs. 25%, and the median time to progression was 12 months vs. 12.5 months, respectively. The positive rate of the clinical benefit response was 59.1% vs. 41.7%, respectively. Toxicities were acceptable in both groups. Conclusion: In this trial, we demonstrated that the gemcitabine-based CCRT and the paclitaxel-based CCRT in combination of doxifluridine are clearly acceptable treatment strategy, and appear more effective than the 5 fluorouracil–based CCRT for locally advanced pancreatic cancer with comparable tolerability. Furthermore, the paclitaxel-based CCRT showed similar efficacy and toxicities to the gemcitabine-based treatment when it was combined with 5-fluorouracil. [Copyright &y& Elsevier]

Purpose: The enzymatic formation of 5-fluorouracil (5-FU) from two fluoropyrimidine prodrugs, doxifluridine (5'-DFUR) and tegafur (FT), was compared in vitro in order to determine whether there are differences between the metabolic profiles of the two prodrugs.Methods: Conversion of the two fluoropyrimidine prodrugs to 5-FU was measured by high-performance liquid chromatography at a concentration of 500 micro M using the microsomal and cytosolic fractions of 12 human livers. The degree of correlation between the 5-FU-forming activities was determined using various cytochrome P450-dependent reactions.Results: Liver microsomes catalyzed 5-FU formation from 5'-DFUR at rates of 10.0-160.1 pmol/min per mg protein and correlated well with CYP2A6-dependent coumarin 7-hydroxylase activity. The rates of microsomal 5-FU formation from FT ranged from 44.9 to 808.3 pmol/min per mg protein and also correlated with coumarin 7-hydroxylase activity. The cytosol fractions catalyzed 5-FU formation from 5'-DFUR at rates of 3,164.6 to 6,026.6 pmol/min per mg protein, almost two orders of magnitude higher than the rates of cytosolic 5-FU formation from FT (46.8-219.0 pmol/min per mg protein).Conclusions: The cytosolic enzymes in livers appear to be important for 5-FU formation from 5'-DFUR. Both cytosolic and microsomal enzymes were involved almost equally in 5-FU formation from FT. The increased formation of 5-FU from 5'-DFUR might provide an answer to the question of why similar blood 5-FU levels were retained despite blood 5'-DFUR levels lower than blood FT levels. [ABSTRACT FROM AUTHOR]

A 58-year-old man was diagnosed as having type 3 gastric cancer (poorly differentiated adenocarcinoma). He underwent total gastrectomy with splenectomy, as well as D3 dissection, and received postoperative chemotherapy combining oral uracil and futrafur (UFT) with cisplatin (CDDP), but results showed recurrence of multiple abdominal lymph node metastases around the aorta. He therefore received various anticancer drug regimens (irinotecan [CPT-11]/CDDP; 1 M tegafur-0.4 M gimeracil-1 M oteracil potassium [TS-1], methotrexate (MTX)/5-fluorouracil); however, final results showed growth of lymph node metastasis and simultaneous worsening of his general condition. The patient then received combined administration of doxifluridine (5′-DFUR)/docetaxel (5′-DFUR, 1000 mg/body [666.7 mg/m 2 ], given by consecutive daily administration, orally, for days 1–14; and docetaxel, 80 mg/body [60 mg/m 2 ], on day 8, by venous drip, every 3 weeks). Three courses of this regimen resulted in approximately 90% reduction of the abdominal lymph node size, disappearance of the right cervical lymph node metastasis, reductions of the levels of two tumor markers (carcinoembryonic antigen [CEA] and carbohydrate antigen [CA]19-9), and improvement of his general condition. In total, seven courses of the regimen were carried out. The patient died on day 298 after starting this combined regimen and showed a response period of 126 days. The primary toxicity identified was neutropenia (grade 4), as well as other low-grade (grade 1, 2) hematological and nonhematological toxicities. In the field of gastric cancer treatment, especially for patients showing multiple resistance to anticancer drugs, an effective therapy is critically needed. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) remains one of the most common neoplasms in the world. Doxifluridine is an oral fluoropyrimidine derivative activated to 5-fluorouracil by uridine phosphorylase which is more expressed in malignant cells. Therefore, we conducted a phase II study to evaluate the activity of oral doxifluridine in patients with advanced hepatocellular carcinoma. Twenty-five advanced hepatocellular carcinoma patients entered the study; doxifluridine was given orally at the initial daily total dose of 2,250 mg for 4 consecutive days every week. All patients are evaluable for toxicity: these included mainly grade 1–2 (WHO) diarrhea, stomatitis, nausea and vomiting; 4 patients (16%) experienced grade 3–4 diarrhea. Twenty-four patients are evaluable for response and 1 complete and 3 partial responses have been observed (response rat 17%, 95% confidence interval: 5–37). Oral doxifluridine at the dose and schedule we used, although having only modest activity in advanced HCC, may represent an alternative to other frequently used chemotherapeutic agents, because of its favorable toxicity profile and its simple route of administration.Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Postoperative adjuvant chemoradiation treatment after curative resection for rectal cancer was needed to reduce recurrence and improve a survival rate. Intravenous 5-fluorouracil (5-FU) and leucovorin has been a mainstay of chemotherapy, but oral 5-FU derivatives have been shown a comparable antitumor activity. Intravenous 5-FU and oral doxifluridine were compared with respect to therapeutic efficacy, drug toxicity, and quality of life. Methods: A total of 166 patients were randomized to receive intravenous 5-FU (450 mg/m2/day) or oral doxifluridine (900 mg/m2/day) in combination with leucovorin (20 mg/m2/day) for depth of invasion, nodal status, metastasis (TNM) stage II and III patients between October 1997 and February 1999. Consecutive daily intravenous infusion for 5 days per every month for a total of 12 cycles (IV arm, n = 74) and oral doxifluridine daily for 3 weeks and 1 week rest for a total of 12 cycles (oral arm, n = 92). Drug toxicity and quality of life were observed. Quality of life was scored according to 22 daily activity items (good, ≥ 71; fair, < 70; poor, < 52). Results: There was no difference of sex between two groups (IV arm: male/female = 45/29, oral arm: male/female = 59/33). The mean age was 52.3 vs. 59.5, respectively. There was also no difference of TNM stage distribution and type of operation between groups ( P = .05). Mean numbers of chemotherapy cycles were 6.5 ± 3.7 (IV arm) vs. 7.2 ± 4.3 (oral arm), respectively. The rate of recurrence was 9/74 (12.1%) in the IV arm and 6/92 (6.5%) in the oral arm, respectively ( P = .937). Local recurrence was 2/74 (stage III; 2.7%) in the IV arm and 1/92 (stage II;1.1%) in the oral arm, respectively. Systemic recurrence was 7/74 (stage III; 9.4%) in the IV arm and 5/92 (stage III; 5.4%) in the oral arm, respectively. The most common site of systemic recurrence was the liver. Toxicity profile was as follows: leukopenia (30/74 vs. 17/92) and alopecia (21/74 vs. 13/92) were statistically more common in the IV arm. Diarrhea was more common in the oral arm. Poor quality of life score between two groups was observed at 1 month (23.9% vs. 13%) and 2 months (15.8% vs. 3.7%) after chemotherapy. Good quality of life score was observed at 1 month (19.5% vs. 49%) and 2 months (47% vs. 72%), respectively ( P < .05). Conclusions: Oral doxifluridine with leucovorin shows a comparable therapeutic efficacy to intravenous 5-FU regimen with high quality of life as postoperative adjuvant therapy. The oral regimen also can be safely given with appropriate toxicity and tolerability. [ABSTRACT FROM AUTHOR]

The disposition kinetics of a new 5-fluorouracil prodrug, 5′-deoxy-5-fluorouridine (5′dFUR, doxifluridine), were investigated in six patients with colorectal carcinoma. Each patient randomly received two single intravenous doses of 5′dFUR (2 and 4 g · m) on separate days. Plasma concentrations of 5′dFUR fell rapidly with terminal half-lives ranging from 16.1 to 27.7 min. A disproportionate increase in the area under the curve with increasing dose was seen in most patients. Doubling the dose resulted in a 40% decrease in nonrenal clearance (0.60 to 0.37 l · min) but no apparent change in renal clearance (0.32 to 0.29 l · min) or steady-state apparent volume of distribution (19.8 to 20.4 l). The mechanism for dose-dependence of 5′dFUR appears to be primarily due to nonlinear elimination associated with nonrenal processes rather than nonlinear plasma protein or tissue binding. [ABSTRACT FROM AUTHOR]

Between January 1993 and October 1995, 34 patients with anthracycline-resistant advanced breast cancer were treated with a combination chemoendocrine therapy of mitoxantrone (MIT), doxifluridine (5′-DFUR) and medroxyprogesterone acetate (MPA). Of 34 patients, 28 were evaluable for efficacy of this combination therapy, and 30 including 2 for whom data were incomplete were assessed for adverse drug reactions. Adriamycin (ADM) was used for pretreatment in 12 patients, 4′-epi-ADM in 6, and THP-ADM in 12. In the eligible patients, 8.0 mg/m2 MIT was administered intravenously every 4 weeks, and 600 mg MPA and 600 mg 5′-DFUR were given orally every day. The median follow-up period was 25 weeks (range 2–90 weeks). The median cumulative dose of mitoxantrone was 66 mg (range 12–121 mg). Of the 28 patients, 11 (39.3%) responded to this combination therapy. As for response in relation to predominant site of lesion, 1 of 5 soft tissue lesions (20%) and 8 of 12 bone metastases (66.7%) showed a partial response, and one complete response and one partial response (25.0%) were seen in eight lung lesions. None of three pleural lesions responded to this therapy. The median duration of response was 31 ± weeks (range 12–82 weeks). Adverse drug reactions were controllable or tolerable. Combined chemoendocrine therapy with a low dose of MIT is a well-tolerated and moderately effective regimen for the treatment of anthracycline-resistant advanced breast cancer. [ABSTRACT FROM AUTHOR]

Thirty-two patients with advanced breast cancer refractory to combination chemotherapy with cyclophosphamide (CPA), doxorubicin (ADR) and 5-fluorouracil (5-FU) (CAF) were treated with the combination of mitomycin C, etoposide, doxifluridine and medroxyprogesterone acetate as second line therapy. Observed responses included 6 patients (18.7%) with complete response (CR) and 7 (21.9%) with partial response (PR). Two (50%) out of 4 patients who had bone pain due to bone metastasis noted pain relief. CR or PR were obtained in 4 out of 12 patients who had not responded to the previous CAF therapy. While grade III myelosuppression was observed in 3 patients, other adverse effects were minimal. It is suggested that this combination therapy may be recommended for advanced breast cancer patients as a second therapy. [ABSTRACT FROM AUTHOR]

• Solubility of doxifluridine in twelve pure solvents was measured. • Solubility data was correlated by λh, van't Hoff, Modified Apelblat, NRTL and UNIQUAC model. • The apparent thermodynamic properties of doxifluridine dissolution in pure solvents were evaluated. In this work, the solubility of doxifluridine in methanol, ethanol, n-propanol, n-butanol, isobutanol, n-Pentanol, n-hexanol, n-octanol, (±)-2-ethyl-1-hexanol, acetone, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) were experimentally determined by a laser dynamic method within the temperature range from 278.15 K to 333.15 K at 101.3 kPa. The measured results demonstrated that the experimental solubility of doxifluridine in all selected pure solvents increased with the rise of temperature. It was also found that the order of the mole fraction solubility of doxifluridine in the twelve mono-solvents was: DMSO > DMF > methanol > acetone > ethanol > n-propanol > n-butanol > n-pentanol > n-hexanol ≈ isobutanol > n-octanol > (±)-2-ethyl-1-hexanol. In order to facilitate the industrial application and other studies, the experimental data of solubility were fitted well using the λh equation, the van't Hoff equation, the modified Apelblat equation, the NRTL model and the UNIQUAC model. Moreover, the apparent thermodynamic properties of doxifluridine in all mono-solvents were investigated by the famous modified Van't Hoff equation from the solubility data. [ABSTRACT FROM AUTHOR]