Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Floxuridine”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1993

Randomized trial of hepatic arterial floxuridine, mitomycin, and carmustine versus floxuridine alone in previously treated patients with liver metastases from colorectal cancer.

PURPOSE: This study was designed to determine if hepatic arterial therapy with floxuridine (F), mitomycin, and carmustine (BCNU) (FMB) is superior to hepatic arterial therapy with F alone in previously treated patients with hepatic metastases from colorectal cancer. PATIENTS AND METHODS: Ninety-five patients were randomized to intrahepatic FMB versus intrahepatic F. All patients had tumor progression after systemic chemotherapy (either therapeutic or adjuvant). RESULTS: There was no significant difference in response rate (47% FMB v 33% F; P = .17). Median survival was similar in the two groups, 19.1 months for the FMB group compared with 14.0 months for the F group (P = .23). The overall median survival was 16.8 months. In patients who received prior adjuvant therapy, there was no difference between the two groups, but response rate was high in both (50% FMB v 62% F). The response rate for all patients who had received only prior adjuvant therapy versus all those who had received prior therapy for metastatic disease was 57% and 35%, respectively (P = .066). In the subset of patients whose disease had progressed with prior systemic chemotherapy, the response rate to FMB was greater than that to F (47% v 23%; P = .035). CONCLUSION: The overall partial response rate of 39% and the overall survival of 16.8 months from initiation of intrahepatitis therapy show that hepatic arterial therapy is a reasonable treatment option for patients whose tumor does not respond to systemic therapy or whose disease progresses after adjuvant therapy for colorectal cancer.

Adult↗
PubMed1994

A phase I/II study of alternating constant rate infusion floxuridine with constant rate infusion vinblastine for the treatment of metastatic renal cell carcinoma.

BACKGROUND: Metastatic renal cell carcinoma (RCC) is largely chemoresistant. The efficacy of cell cycle specific chemotherapeutic agents, particularly those with short half-lives, may be enhanced by the use of constant rate infusion schedules. Infusional floxuridine has been demonstrated to have a response rate of approximately 20%. Infusional vinblastine has not been tested extensively in patients with metastatic RCC. The sequential use of these agents was designed to increase efficacy and limit toxicity. METHODS: Fifteen patients with metastatic RCC were treated with constant rate infusion floxuridine, 0.075 mg/kg/day for 14 days, followed by a constant rate infusion of vinblastine, 0.7 mg/m2/day for 14 days. The cycle repeated every 28 days and floxuridine and vinblastine doses were incrementally increased until the maximum tolerated dose (MTD) for each patient was reached. RESULTS: Four patients had partial responses (27%), which were maintained for 3, 9, 16 and 19+ months, whereas five patients had stable disease for 3-15 months. Median survival from initiation of therapy was 379 days. Three of four responses occurred in nonpulmonary locations, and all responses occurred in patients who had a prior nephrectomy. MTD for floxuridine was 0.1 mg/kg/day and for vinblastine, 0.7 mg/m2/day. Toxic reaction to floxuridine was limited to diarrhea, whereas the principle dose-limiting toxic reaction for vinblastine was neutropenia. Catheter-related complications were also observed. CONCLUSIONS: Alternating constant rate infusion floxuridine and constant rate infusion vinblastine is active in the treatment of metastatic RCC. Whether this regimen is superior to infusional floxuridine is undetermined. Although the toxicity associated with this regimen is manageable, it appears to be more severe than that reported with infusional floxuridine alone.

Adult↗
PubMedDate not supplied

Extrahepatic biliary stenoses after hepatic arterial infusion (HAI) of floxuridine (FUdR) for liver metastases from colorectal cancer.

Hepatic arterial infusion of floxuridine is an effective treatment for unresectable hepatic metastases from colorectal cancer. Despite its pharmacological advantage of higher tumor drug concentration with minimal systemic toxicity, hepatic arterial infusion of floxuridine is characterized by regional toxicity, including hepatobiliary damage resembling idiopathic sclerosing cholangitis (5-29% of treated cases). Unlike previous reports describing biliary damage of both intrahepatic and extrahepatic ducts, a case series of extrahepatic biliary stenosis after hepatic arterial infusion with floxuridine is herein described. Between September 1993 and February 1999, 54 patients received intraarterial hepatic chemotherapy based on continuous infusion of floxuridine (dose escalation 0.15-0.30 mg/kg/day for 14 days every 28 days) plus dexamethasone 28 mg. Twenty-seven patients underwent laparotomy to implant the catheter into the hepatic artery, the other 27 patients receiving a percutaneous catheter into the hepatic artery through a transaxillary access. Five patients (9.2%) developed biliary toxicity with jaundice and cholangitis (3 cases), alterations of liver function tests and radiological features of biliary tract abnormalities. They received from 9 to 19 cycles (mean 14.5 +/- 6.3 cycles) of floxuridine infusion with a total drug delivered dose ranging from 20.3 to 41.02 mg/kg (mean: 31.4 +/- 13.5 mg/kg). Extrahepatic biliary sclerosis was discovered by computed tomography scan and ultrasound, followed by endoscopic retrograde cholangiopancreatography and/or percutaneous cholangiography in 3 cases. Radiological findings included common hepatic duct complete obstruction in 1 case, common hepatic duct stenosis in 2 cases, common bile duct obstruction in 1 case, and intrahepatic bile ducts dilation without a well-recognized obstruction in 1 case. Two patients were treated by sequentially percutaneous biliary drainage and balloon dilation while 1 patient had an endoscopic transpapillary biliary prosthesis placed. Percutaneous or endoscopic procedures obtained the improvement of hepatic function and cholestatic indexes without subsequent jaundice or cholangitis. In two patients suppression of floxuridine infusion allowed the improvement of hepatic function. The present series suggests that in some patients receiving hepatic arterial infusion of floxuridine extrahepatic biliary stenosis may represent the primary event leading to a secondary intrahepatic biliary damage that does not correlate with specific floxuridine toxicity but results from bile stasis and infection, recurrent cholangitis and eventually biliary sclerosis. Aggressive research for extrahepatic biliary sclerosis is advised, since an early nonsurgical treatment of extrahepatic biliary stenosis may prevent an irreversible intrahepatic biliary sclerosis worsening the prognosis of metastatic liver disease.

Adenocarcinoma↗
PubMed1993

Alpha-2B-interferon plus floxuridine in metastatic renal cell carcinoma. A phase I-II study.

BACKGROUND: Both alpha-interferon and floxuridine are active in metastatic renal cell carcinoma (MRCC); the two agents have demonstrated antitumor synergism and different clinical toxicities. The purpose of this study was to determine the maximum tolerable dose (MTD) of floxuridine (FUDR), administered as a constant continuous infusion for 14 days every 28 days, in combination with fixed doses of alpha-2B-interferon and to preliminarily evaluate the antitumor activity of this combination. METHODS: Sixteen patients entered the study; six had previously received alpha-interferon. Alpha-2B-interferon was administered at the dose of 10 x 10(6) IU intramuscularly 3 times/week and floxuridine at the starting daily dose of 0.075 mg/kg. This dose was escalated at each subsequent cycle up to dose-limiting toxicity. RESULTS: Most common toxicities included fever and flue-like symptoms, fatigue, anorexia, diarrhea, mucositis, and nausea, and 55% of patients experienced greater than or equal to Grade 2 toxicity, mostly diarrhea, for floxuridine doses greater than 0.125 mg/kg/d. Among 15 evaluable patients, 1 achieved a complete response and 4 achieved a partial one (33%; 95% confidence interval, 12-62%). Three partial responses were obtained in patients pretreated with alpha-interferon plus vinblastine. CONCLUSIONS: The combination of alpha-2B-interferon and floxuridine is feasible, and in our regimen the recommended daily dose of floxuridine for Phase II studies was 0.125 mg/kg. This combination is active in metastatic renal carcinoma, but further studies are needed to determine whether alpha-2B-interferon has added anything to the FUDR infusion or vice versa.

Adult↗
PubMed2005

Floxuridine amino acid ester prodrugs: enhancing Caco-2 permeability and resistance to glycosidic bond metabolism.

PURPOSE: The aim of this study was to synthesize amino acid ester prodrugs of 5-fluoro-2'-deoxyuridine (floxuridine) to enhance intestinal absorption and resistance to glycosidic bond metabolism. METHODS: Amino acid ester prodrugs were synthesized and examined for their hydrolytic stability in human plasma, in Caco-2 cell homogenates, and in the presence of thymidine phosphorylase. Glycyl-L: -sarcosine uptake inhibition and direct uptake studies with HeLa/PEPT1 cells [HeLa cells overexpressing oligopeptide transporter (PEPT1)] were conducted to determine PEPT1-mediated transport and compared with permeability of the prodrugs across Caco-2 monolayers. RESULTS: Isoleucyl prodrugs exhibited the highest chemical and enzymatic stability. The prodrugs enhanced the stability of the glycosidic bond of floxuridine. Thymidine phosphorylase rapidly cleaved floxuridine to 5-fluorouracil, whereas with the prodrugs no detectable glycosidic bond cleavage was observed. The 5'-L: -isoleucyl and 5'-L: -valyl monoester prodrugs exhibited 8- and 19-fold PEPT1-mediated uptake enhancement in HeLa/PEPT1 cells, respectively. Uptake enhancement in HeLa/PEPT1 cells correlated highly with Caco-2 permeability for all prodrugs tested. Caco-2 permeability of 5'-L: -isoleucyl and 5'-L: -valyl prodrugs was 8- to 11-fold greater compared with floxuridine. CONCLUSIONS: Amino acid ester prodrugs such as isoleucyl floxuridine that exhibit enhanced Caco-2 transport and slower rate of enzymatic activation to parent, and that are highly resistant to metabolism by thymidine phosphorylase may improve oral delivery and therapeutic index of floxuridine.

Amino Acids↗
PubMed2006

Coencapsulation of irinotecan and floxuridine into low cholesterol-containing liposomes that coordinate drug release in vivo.

A liposomal delivery system that coordinates the release of irinotecan and floxuridine in vivo has been developed. The encapsulation of floxuridine was achieved through passive entrapment while irinotecan was actively loaded using a novel copper gluconate/triethanolamine based procedure. Coordinating the release rates of both drugs was achieved by altering the cholesterol content of distearoylphosphatidylcholine (DSPC)/distearoylphosphatidylglycerol (DSPG) based formulations. The liposomal retention of floxuridine in plasma after intravenous injection was dramatically improved by decreasing the cholesterol content of the formulation below 20 mol%. In the case of irinotecan, the opposite trend was observed where increasing cholesterol content enhanced drug retention. Liposomes composed of DSPC/DSPG/Chol (7:2:1, mole ratio) containing co-encapsulated irinotecan and floxuridine at a 1:1 molar ratio exhibited matched leakage rates for the two agents so that the 1:1 ratio was maintained after intravenous administration to mice. The encapsulation of irinotecan was optimal when copper gluconate/triethanolamine (pH 7.4) was used as the intraliposomal buffer. The efficiency of irinotecan loading was approximately 80% with a starting drug to lipid molar ratio of 0.1/1. Leakage of floxuridine from the liposomes during irinotecan loading at 50 degrees C complicated the ability to readily achieve the target 1:1 irinotecan/floxuridine ratio inside the formulation. As a result, a procedure for the simultaneous encapsulation of irinotecan and floxuridine was developed. This co-encapsulation method has the advantage over sequential loading in that extrusion can be performed in the absence of chemotherapeutic agents and the drug/drug ratios in the final formulation can be more precisely controlled.

Animals↗
PubMed1989

Stability of floxuridine and leucovorin calcium admixtures for intraperitoneal administration.

The stability of floxuridine and leucovorin calcium in admixtures of 0.9% sodium chloride injection at various concentrations, temperature conditions, and time points was determined. Admixtures of floxuridine and leucovorin calcium were prepared in 1-L plastic bags containing 0.9% sodium chloride injection. Admixtures containing the following three concentrations were prepared: floxuridine 1 g and leucovorin calcium 30 mg, floxuridine 2 g and leucovorin calcium 240 mg, and floxuridine 4 g and leucovorin calcium 960 mg. The admixtures were stored at refrigerated temperature (4-8 degrees C), ambient room temperature (20 degrees C), and near-physiologic body temperature (40 degrees C). Drug concentrations were measured with a stability-indicating high-performance liquid chromatographic (HPLC) method at 0, 4, 8, 24, and 48 hours (4-8 degrees C) and at 0, 1, 3, 6, 24, and 48 hours (20 degrees C and 40 degrees C). A second set of samples at the same concentrations was prepared and sequentially stored at refrigerated, room, and near-physiologic temperatures to simulate actual-use conditions; these samples were assayed by HPLC at 0, 4, 8, 24, and 48 hours (4-8 degrees C); 49, 51, 54, and 60 hours (20 degrees C); and 61, 63, 66, and 72 hours (40 degrees C). All solutions were protected from light. Floxuridine and leucovorin calcium were stable at each concentration and temperature condition tested for a minimum of 48 hours. However, leucovorin calcium was more subject to decomposition at near-physiologic temperature than at other temperatures, with the most degradation at the lowest concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromatography, High Pressure Liquid↗
PubMed1993

A phase II study of constant-infusion floxuridine for the treatment of metastatic renal cell carcinoma.

BACKGROUND: Twenty-nine patients with metastatic renal cell carcinoma (RCC) were treated with constant-infusion floxuridine (FUdR, Roche Laboratories, Nutley, NJ). METHODS: The initial dosage was 0.075 mg/kg/day for 14 days every 28 days and was increased or decreased by 0.025-mg/kg/day increments at each subsequent cycle until the maximum tolerated dose (MTD) was achieved. RESULTS: All patients were fully assessable. One (4%) patient had a complete response, 5 (17%) had a partial response, 13 (50%) had stabilized disease, and 10 (34%) had progressive disease. The treatment-limiting toxic effect was diarrhea, and the median tolerated dosage was 0.1 mg/kg/day for 14 days every 28 days (range, 0.05-0.275 mg/kg/day). Five of the six responses occurred at a dosage of 0.1 mg/kg/day or less, which was achievable in most patients. Patients who reached their MTD without achieving a complete or partial response were switched to circadian-infusion floxuridine to determine whether an increased dose intensity could be administered and whether this would translate into additional responses. A higher median tolerated dosage of 0.15 mg/kg/day was achieved with circadian administration; however, no additional responses were observed. The median survival time was 891 days after the diagnosis of metastatic RCC and 445 days after the institution of floxuridine therapy. CONCLUSIONS: Constant-infusion floxuridine is active against metastatic RCC and produces a response rate that appears to be comparable to that of circadian administration of floxuridine.

Adult↗
PubMed1994

Quality of life and survival with continuous hepatic-artery floxuridine infusion for colorectal liver metastases.

Very few patients with liver metastases from colorectal cancer can be cured. We have investigated whether a treatment to slow the growth of liver metastases, hepatic-artery infusion of floxuridine, improves palliation in this setting. In a randomised study of 100 patients, we compared quality of life and survival in patients who received hepatic-artery infusion of floxuridine and in those who received conventional symptom palliation. 95% of control patient survival time was spent with normal quality-of-life scores, which suggests that the aim of treatment should be to prolong normal-quality survival rather than merely to sustain quality of life. There was a significant prolongation (p = 0.03) in overall survival in floxuridine-treated patients compared with controls (median 405 vs 226 days). There were similar significant prolongations in normal-quality (ie, normal symptom scores) survival for physical symptoms (p = 0.04), anxiety (p = 0.04), and depression (p = 0.04). This survival benefit was associated with significant reductions in metastasis size on computed tomography (p = 0.001) and in serum carcinoembryonic antigen concentration (p = 0.006) in floxuridine-treated patients. There was no evidence of treatment-related hepatotoxicity as assessed by serum aspartate aminotransferase and bilirubin measurements. This is the first demonstration that survival can be prolonged with normal quality of life in patients with colorectal liver metastases. We conclude that hepatic-artery floxuridine infusion can be recommended for suitable patients.

Anxiety↗
PubMed2002

Floxuridine coupling with lactosaminated human albumin to increase drug efficacy on liver micrometastases.

BACKGROUND: Conjugates of nucleoside analogues with galactosyl terminating peptides selectively enter hepatocytes through the asialoglycoprotein receptor. After intracellular release from the carrier, the drugs partly exit from hepatic cells into hepatic blood. AIMS: To establish whether administration of a conjugate of floxuridine with lactosaminated human albumin selectively enhances drug concentrations in hepatic blood. Floxuridine is a fluoropyrimidine active on human colorectal cancer, a tumour which metastasises first to the liver. METHODS: In rats injected with free or conjugated floxuridine, plasma levels of the drug were determined in hepatic veins and in inferior vena cava, in order to measure drug concentrations in hepatic blood and in the systemic circulation, respectively. RESULTS: Ratios between floxuridine levels in hepatic veins and those in systemic circulation were found to be seven times higher in rats injected with the conjugate (p=0.000). CONCLUSIONS: The present results suggest that coupling to lactosaminated albumin might improve the effect of floxuridine in adjuvant chemotherapy of colorectal cancer by exposing the cells of liver micrometastases (nourished by hepatic sinusoids) to enhanced drug concentrations.

Animals↗
PubMedDate not supplied

Intrahepatic chemotherapy with floxuridine, leucovorin and dexamethasone in continuous infusion and mitomycin-C bolus in unresectable hepatic metastases from colorectal cancer: a phase II study.

BACKGROUND: Intrahepatic continuous infusion FUDR induces a 50% response rate in patients with hepatic metastases from colorectal cancer. Lower rates have been observed in pretreated patients. The combination of floxuridine plus leucovorin has obtained over 70% responses, with high hepatic toxicity. The use of dexamethasone can decrease hepatic toxicity. A randomized study reported an increase in response rate and a decrease in hepatic toxicity in a group of patients treated with floxuridine plus dexamethasone compared to a group receiving only floxuridine. Moreover, the combination of mitomycin C, carmustine and floxuridine is also effective in pretreated patients. METHODS: On such premises, since July 1993 we have treated 39 patients affected by unresectable hepatic metastases from colon carcinoma (26 patients) and rectal carcinoma (13 patients) with the combination continuous infusion of floxuridine (0.20 mg/kg per day) + leucovorin (7.5 mg/m2/day) + dexamethasone (20 mg on days 1 to 14) and bolus mitomycin C (10 mg/m2 on day 1) via the hepatic artery. Cycles were administered every four weeks. There were as 28 males and 11 females, with a median age of 64 years (range, 39-75) and a median PS = 0. Twenty-two patients were pretreated with systemic chemotherapy including 5-fluorouracil plus leucovorin. Total number of cycles was 189, with a median of 6 cycles per patient (range, 1-12). RESULTS: Of 39 patients 37 were assessable for response (2 patients were not assessable because they stopped chemotherapy for occlusion of the catheter after the first cycle). There were 3 complete responses (1 in a naive patient and 2 in pretreated patients), 16 partial responses (11 in pretreated patients and 5 in chemonaive patients), 4 minor responses, 4 stable disease and 10 progressive disease. The overall response rate was 51.3% (95 Cl, 51.3-86.7%). Median time to progression was 6 months (range, 1-34+). Overall survival was 18 months (range, 1-34+). Of 39 patients, 36 were assessable for toxicity (WHO) (3 patients died after the first cycle for progression of disease): diarrhea and nausea-vomiting grade 3-4 occurred respectively in 15 (41%) and 3 patients (8%); hepatic toxicity was mild. CONCLUSIONS: The treatment we used showed an elevated activity in liver metastases from colorectal cancer even in patients pretreated and resistant to systemic chemotherapy, although toxicity grade 3-4 diarrhea occurred in approximately 40% of the patients.

Adult↗
PubMed1990

Intra-arterial floxuridine vs systemic fluorouracil for hepatic metastases from colorectal cancer. A randomized trial.

Seventy-four patients with liver metastasis from proved colorectal primary adenocarcinoma were entered into a prospective, randomized clinical trial to evaluate treatment with intra-arterial floxuridine compared with standard outpatient therapy with fluorouracil delivered by intravenous bolus injection. Eligible patients were randomized to hepatic arterial chemotherapy with an implanted infusion pump or systemic chemotherapy. No crossover between treatment arms was permitted, and patients were followed up to progression and death. Objective tumor response was observed in 48% of patients receiving intra-arterial floxuridine and in 21% of patients receiving intravenous fluorouracil. Time to hepatic progression was significantly longer in the group given intra-arterial therapy: 15.7 vs 6.0 months. However, time to overall progression (6.0 vs 5.0 months) and survival (12.6 vs 10.5 months) were not statistically different. Based on these data, we cannot recommend treatment with intra-arterial floxuridine as given in this study for metastatic colorectal cancer to the liver.

Adenocarcinoma↗
PubMed1994

Gastric mucosal injury after hepatic arterial infusion chemotherapy with floxuridine. A clinical and pathologic study.

BACKGROUND: Hepatic arterial infusion chemotherapy (HAIC) of liver metastases of colon cancer with an implantable pump is associated with liver and gastrointestinal complications. METHODS: The authors retrospectively studied the clinical features and gastric histopathology of nine patients who received HAIC and had gastritis develop and in whom biopsy specimens were available. RESULTS: Gastritis was heralded in these patients by epigastric pain and tenderness, nausea, vomiting, weakness, and anorexia. In seven patients, 18 gastric ulcers were endoscopically detected. Mucosal damage developed despite prophylactic antiulcer therapy and healed only upon cessation of HAIC. These observations suggest that the predominant drug given, floxuridine, was the responsible toxic agent. Seventeen biopsy specimens were reviewed, and all exhibited varied histologic evidence of inflammation, reactive glandular changes, and cell necrosis. These mucosal changes were present even in tissues obtained from patients without ulcers. In addition, floxuridine-induced glandular atypia was noted in eight biopsy samples from six patients. The crowded glands were distorted and lined by large cells that included bizarre forms with pleomorphic nuclei. CONCLUSIONS: Gastric injury in HAIC appeared analogous to the general features encountered in reactive gastritis resulting from chemical irritants. The glandular atypia is peculiar to HAIC, and although the changes were morphologically alarming, in this clinical situation care should be exercised not to interpret floxuridine-induced atypia as carcinoma.

Adult↗
PubMed1989

Floxuridine-induced sclerosing cholangitis: an ischemic cholangiopathy?

A 43-year-old man underwent abdominoperineal resection of a rectal adenocarcinoma, and left hepatic lobectomy for a single metastasis. He then received hepatic artery infusions of floxuridine. The tumor did not recur, but sclerosing cholangitis and liver failure developed which necessitated orthotopic liver transplantation. In the hilus of the native liver, obstructive arteriopathy and portal venopathy were found. These lesions probably had been caused by drug-induced intravascular thrombosis. Thus, the sclerosing cholangitis that develops in many patients after floxuridine infusion may be ischemic rather than toxic. The patient described here is well, 14 months after orthotopic liver transplantation. Therefore, in some cases of floxuridine-induced cholangitis, liver transplantation appears to be indicated despite a history of metastasizing carcinoma.

Adult↗
PubMed1975

Effect of deoxyuridine coadministration on toxicity and antitumor activity of fluorouracil and floxuridine.

The addition of deoxyuridine (UDR) to fluorouracil (FU) or floxuridine (5-fluoro-2' deoxyuridine) (FUDR) produced a substantial increase in their toxicity in BDF1 mice. Antitumor assays using sarcoma 180 tumor-bearing mice showed a concomitant increase in tumor growth inhibition for the nucleoside-drug combination over identical doses of the single drug. However, no significant increase in antitumor activity with the combination treatment was demonstrated when equitoxic doses were given. Additional support for the therapeutic equality of the single and combination drug regimens was the similarity of the therapeutic indexes for each treatment regimen involving either fluorouracil or floxuridine. The results suggested that any therapeutic benefit achieved with the combination therapy could be duplicated with either fluorouracil or floxuridine at a higher dose.

Animals↗
PubMed1999

Local disposition kinetics of floxuridine after intratumoral and subcutaneous injection as monitored by [19F]-nuclear magnetic resonance spectroscopy in vivo.

PURPOSE: To test the utility of [19F]-nuclear magnetic resonance (NMR) spectroscopy for studying the kinetics of local drug disposition after interstitial application in vivo. METHODS: Floxuridine at 30 micromol (2.5% of the reported i.p. 50% lethal dose, LD50) was injected into rats either intratumorally (Morris hepatoma M3924A) or s.c. [19F]-NMR spectra were obtained at the site of administration for up to 5 h after injection using a 2-cm diameter surface coil at 2.0 T. Signal-time data obtained for floxuridine and the metabolite 5-fluorouracil were analyzed using linear compartment models. RESULTS: The lower limit for the quantitation of drug remaining at the site of administration was 1 micromol for tumors and 0.2 micromol for the s.c. injection site. Local drug disposition was biexponential in four of six tumors where the half-lives of the fast and slow components of disposition ranged from 4 to 26 and from 33 to 289 min, respectively. It was monoexponential in the remaining two tumors (half-lives 49 and 128 min) and in the s.c. injection experiments (n = 4, half-life 6-9 min). 5-Fluorouracil could be quantitated in three of six tumors; the estimated fraction of floxuridine converted intratumorally into 5-fluorouracil was 11-23%. Alpha-fluoro-beta-alanine was detected in the sum spectra of three of the six tumours. CONCLUSIONS: Local drug-disposition kinetics after interstitial application can be monitored noninvasively by in vivo [19F]-NMR spectroscopy. Disposition kinetics after local injection is highly variable and has a slow component in this tumor, whereas it is much less variable and relatively fast in subcutaneous tissue. The results suggest that NMR spectroscopy may be useful for in vivo studies of drug release from depot preparations designed for interstitial application.

Animals↗
PubMed2001

P53 mutation and response to hepatic arterial floxuridine in patients with colorectal liver metastases.

PURPOSE: To establish the relationship between the number and site of p53 genomic mutations in metastatic colorectal cancer, and the response to hepatic arterial floxuridine. METHODS: Liver metastasis biopsies were collected, at the time of laparotomy for hepatic arterial cannulation. in 28 patients with metachronous colorectal liver metastases. p53 Gene mutations were assessed using reverse transcription, nested polymerase chain reaction, single strand conformational polymorphism and gene sequencing. Chemotherapy response was determined from computerised liver tomograms after 4 months of treatment. RESULTS: Liver metastasis p53 mutation was identified in 21 (75%), and p53 "hot spot" mutation in 11 (39%) patients. There was a significantly lower prevalence (Fisher's, P=0.001) of patients with p53 "hot spot"-mutated liver metastases in stable disease and partial response (5/22) than in progressive (6/6) disease groups. Significantly fewer (Mann-Whitney U, P=0.002) p53 "hot spot" mutations/biopsy were observed in liver metastases from stable disease and partial response (median 0, iqr. 0-0) than in progressive (median 1, iqr 1-2) disease patients. p53 "Hot spot"-mutated liver metastases were associated with significantly shorter survival times (logrank P=0.05) after hepatic arterial floxuridine. Significant response or survival-time differences by total or L2/L3 zinc-binding site p53 mutations were not detected. CONCLUSIONS: The results support a role for p53 "hot spot" mutations in colorectal liver metastasis resistance to fluorinated pyrimidines, and suggest that the presence of such mutations may be a contra-indication to treatment of colorectal liver metastases with hepatic arterial floxuridine.

Adult↗
PubMed1991

High-performance liquid chromatographic method for the simultaneous measurement of floxuridine and fluorouracil in human body fluids.

A method for the simultaneous measurement of floxuridine (5-fluorodeoxyuridine) and fluorouracil in human plasma and peritoneal fluid has been developed. This method utilizes high-performance liquid chromatographic analysis with a Zorbax RX column (25 cm x 4.6 mm I.D.) plus a guard cartridge of the same material. The sensitivity limits for this assay are 0.25 mumol/l in a 20-microliters sample. The detection limit at a signal-to-noise ratio of 3 is 2.5 nmol/l. This procedure has been used to quantitatively measure concentration versus time profiles of floxuridine and fluorouracil in plasma and peritoneal fluid of human patients after receiving intraperitoneal administration of floxuridine.

Ascitic Fluid↗