Weekly paclitaxel in combination with doxifluridine for peritoneally disseminated gastric cancer with malignant ascites.

BACKGROUND: The efficacy of systemic chemotherapy for peritoneal dissemination of gastric cancer remains unclear. The efficacy of weekly paclitaxel in combination with doxifluridine (5'-DFUR) in gastric cancer patients with malignant ascites was evaluated. PATIENTS AND METHODS: Patients with histologically confirmed gastric cancer with ascites were eligible. The treatment consisted of paclitaxel intravenously (i.v.) administered at 80 mg/m(2) on days 1, 8 and 15 every 4 weeks, and doxifluridine administered orally at 533 mg/m(2) on days 1-5 every week. The response rate for patients with ascites was determined based on the Japanese Classification of Gastric Carcinoma. Also, the concentration of paclitaxel in the ascites was measured. RESULTS: Twenty-four patients were investigated. The response rate (RR) was 41.7%, including complete remission (CR) and partial remission (PR) in 4 and 6 patients, respectively. The concentration of paclitaxel in the ascites was maintained between 0.01 µM and 0.05 µM until 72 hours. The median overall survival (OS) was 215 days, and 1-year survival rate was 29.2%. No severe toxicity was noted. CONCLUSION: Weekly paclitaxel in combination with doxifluridine is effective for gastric cancer patients with malignant ascites with an acceptable toxicity profile.

A phase II study of weekly paclitaxel and doxifluridine combination chemotherapy for advanced/recurrent gastric cancer.

BACKGROUND: Paclitaxel and doxifluridine (5'-DFUR) have distinct mechanisms of action and toxicity profiles. This study evaluated the antitumor activity and toxicities of combination chemotherapy with these drugs in patients with advanced/recurrent gastric cancer (AGC). PATIENTS AND METHODS: Patients with histologically confirmed AGC, which was either unresectable or metastatic, were included in this study. The treatment consisted of 80 mg/m² paclitaxel given i.v. on days 1, 8, and 15 every 4 weeks, and 533 mg/m² doxifluridine given orally on days 1-5 every week. RESULTS: One hundred and four patients were evaluated for toxicity and 93 patients were evaluated for a therapeutic response. The overall response rate was 33.3% (1st line: 41.7%, 2nd line: 25.0%), including a complete remission in two patients, a partial remission in 29, stable disease in 39, progressive disease in 17; the response was not evaluable in six patients. The median overall survival was 287 days. Commonly observed grade 3/4 adverse events were leukopenia (13.5%), anorexia (3.8%), fatigue (3.8%) and diarrhea (2.9%). CONCLUSION: Paclitaxel and doxifluridine combination chemotherapy is a well-tolerated and convenient treatment regimen that can be given on an outpatient basis with promising efficacy for AGC.

A combination phase I study of weekly paclitaxel and doxifluridine in advanced gastric cancer patients.

BACKGROUND: Preclinical studies have shown that paclitaxel and doxifluridine can act synergistically without overlapping toxicity for the treatment of advanced gastric cancer. The objectives of this study were to determine the maximum tolerated dose (MTD), the dose-limiting toxicity and the recommended Phase II dose for this drug combination. PATIENTS AND METHODS: Patients with histologically confirmed gastric cancer were eligible for the study. The paclitaxel dose (days 1, 8, 15) was augmented with a fixed dose of for treatments (1-3). doxifluridine (533 mg/m2, 5 days/week) on a 28-day cycle. RESULTS: Eighteen patients were enrolled. The MTD was not reached until the highest dose level. One patient had Grade 3 myelosuppression. The responses of the 13 suitable patients included 1 complete response and 5 partial responses. CONCLUSION: Although the MTD level could not be definitively which is a established, upon consideration of the lengthy administration time and the effectiveness, the recommended Phase II dose of paclitaxel was concluded to be 80 mg/m2 in combination with doxifluridine at 533 mg/m2.

The effect of FR167653 in a canine total hepatic vascular exclusion model.

BACKGROUND/AIMS: Though liver grafts from non-heart-beating donors are now attracting much attention, these grafts inevitably suffer from severe warm ischemia. The aim of this study was to evaluate the effect of TNF-alpha and IL-1 suppression on warm ischemia-reperfusion injury in a canine total hepatic vascular exclusion model. METHODOLOGY: Warm ischemia was induced by 1-h total hepatic vascular exclusion with active splenofemuro-juglar bypass. Animals were divided into two groups. FR167653 (1 mg/kg/hr) was administered via the portal vein from 30 min prior to ischemia until 2 h after reperfusion to the FR group (n = 7), and a vehicle was administered to the control group (n = 7). The serum alanine aminotransferase, aspartate amino-transferase, lactate dehydrogenase, and hyaluronic acid levels were measured. Hepatic tissue blood flow was also measured. Liver specimens were harvested for histological study, and polymorphonuclear neutrophils were counted. RESULTS: Serum liver enzymes were significantly (p < 0.05) lower, and hepatic tissue blood flow was kept significantly (p < 0.05) better in the FR group than in the control. Histological tissue damage was mild, and polymorphonuclear neutrophil infiltration was significantly (p < 0.05) lower in the FR group than in the control group. CONCLUSIONS: FR167653 provides protective effects on hepatic warm ischemic injury in a canine total hepatic vascular exclusion model.

Advantages of Celsior solution in graft preservation from non-heart-beating donors in a canine liver transplantation model.

BACKGROUND: The optimal method for preserving livers from non-heart-beating donors (NHBD) is still unknown. We compared the Celsior solution, a new extracellular-type, low-potassium, low-viscosity preservation solution, with the University of Wisconsin (UW) solution in a canine orthotopic liver transplantation from NHBD. MATERIALS AND METHODS: Fourteen adult mongrel dogs, weighing 9 to 17 kg, were divided into two groups: the Celsior or the UW group (n = 7 each). The thoracic descending aorta and supradiaphragmatic inferior vena cava were cross-clamped for 20 min to induce warm ischemia as a NHBD model. The liver was flushed with the respective cold preservation solution and then stored at 4 degrees C for 4 h. The grafts were transplanted using the piggy-back technique under portal decompression by leaving the native right lobe as a temporary shunt. RESULTS: The duration of liver flushing out (min) was shorter (P < 0.05), and the serum glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, lactate dehydrogenase, lactate, and alpha-glutathione S-transferase concentrations 2 and 6 h after reperfusion of the graft (RPF) were lower (P < 0.05) in the Celsior group than in the UW group. Hepatic tissue blood flow (HTBF) did not deteriorate as much (P < 0.05) in the Celsior group. The serum endothelin-1 level was lower (P < 0.05) in the Celsior group 2 h after RPF. Histopathology of liver specimens revealed portal congestion and hepatocyte necrosis with neutrophil infiltration in the UW group, while these findings were mild in the Celsior group. CONCLUSIONS: The Celsior solution improves vascular endothelial injury in livers from NHBDs and may have advantages in graft flush and preservation of grafts from NHBDs.

FR128998 (a PAF Receptor Antagonist) Counters the Increased Pulmonary Vascular Resistance Associated with Ischemia-Reperfusion Injury in the Canine Lung.

Ischemia-reperfusion injury induces deterioration of pulmonary function following lung transplantation. The spiro-thiazepin derivative FR128998 (FR) is a novel PAF receptor antagonist. The effect of FR on ischemia-reperfusion injury was investigated in an in situ warm ischemia model of canine lungs. Fifteen adult mongrel dogs, weighing 6 to 12 kg, were divided into two groups. FR (1 mg/kg/hr) was administered from prior to ischemia until 2 hours after reperfusion (FR-treated group; n = 8), or vehicle was injected using the same technique (Control group; n = 7). Following hilar stripping of the left lung, the left pulmonary artery and veins were clamped for 3 hours to induce warm ischemia. The left main bronchus was bisected at the same time and anastomosed 3 hours later. Arterial oxygen saturation (SaO(2)), left pulmonary vascular resistance (L-PVR), and cardiac output (CO) were measured 30 minutes after reperfusion. The lungs were harvested for pathological study, and polymorphonuclear neutrophils (PMNs) were counted. The 2-day survival rate was also investigated. After reperfusion, SaO(2) L-PVR, and CO were significantly (p < 0.05) better in the FR-treated group than in the control group. Histological findings after 30 minutes of reperfusion showed alveolar damage with interstitial edema and hyaline membranes localized along the alveolar ducts in the control group, while there was only slight localized interstitial edema in the FR group. PMN infiltration was less extensive in the FR group than in the control group. FR appears to have a protective effect against lung ischemia-reperfusion injury. This might result from inhibition of the local release of PAF.