DNA synthesis; Bacterial; HSV; CMV

Liver metastases are mainly supplied by the hepatic artery. Sustained high levels of intratumoral drug are achievable with certain drugs given via the hepatic artery. Floxuridine (FUDR) is an ideal drug for hepatic arterial infusion (HAI) due to its short half life, steep dose response curve, high total body clearance, and high hepatic extraction. HAI FUDR has consistently shown higher response rates than systemic chemotherapy alone, and some studies have shown a survival advantage. HAI FUDR in combination with systemic chemotherapy has evolved over the years and may be used in palliative, neoadjuvant, and adjuvant settings. The dramatic responses observed with HAI FUDR plus modern era systemic chemotherapy offer the possibility of resection and cure in selected patients. The high hepatic extraction of FUDR limits systemic side effects. Toxicity includes biliary and gastrointestinal ulcers. [5]

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HAI Floxuridine (FUDR) both alone and in combination with systemic chemotherapy has resulted in high response rates, longer hepatic progression-free survival, and increasing resection rates for unresectable liver disease from CRC. Flouropyrimidine have been the cornerstone of CRC treatment for more than 50 years. A good way to deliver these drugs, especially FUDR, to a patient with liver metastases from CRC is via HAI. Modern implantable HAI pumps have low rates of immediate and long term complications. The combination of HAI FUDR with modern systemic chemotherapy is an effective way to treat such patients with liver metastases. In the adjuvant setting HAI FUDR and systemic chemotherapy combinations can increase disease-free survival and hepatic disease-free survival. The studies were not powered to look at overall survival. Consideration should be given to placing an HAI pump at the time of liver resection and treating with adjuvant HAI FUDR plus systemic chemotherapy. If the liver disease is unresectable and a trial of systemic chemotherapy with or without biologic agents, e.g., bevacizumab or cetuximab, fails to make the liver resectable, then HAI plus systemic chemotherapy should be considered. HAI FUDR/Dex combined with modern systemic chemotherapy has a role in the treatment of liver metastases from CRC [5].

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Floxuridine (5'-fluorodeoxyuridine, FUdR) acts as an inhibitor of DNA replication by binding to thymidylate synthase and is widely used to treat colorectal cancer. FUdR is also frequently used in research on aging in C. elegans since by blocking reproduction it allows maintenance of synchronous nematode populations. Here researchers examine age-specific effects of exposure to 50 μM FUdR on pathology and mortality. Researchers report that initiating exposure to FUdR at late development or early adulthood reduces lifespan but later initiation increases it. Moreover, earlier initiation leads to enhancement of senescent intestinal atrophy, but amelioration of several other senescent pathologies (pharyngeal degeneration and uterine tumors). These results provide further evidence of the complex effects of FUdR on aging in C. elegans, and therefore support the argue against its routine use in studies of nematode aging due to its possible confounding effects. However, they also illustrate how effects of FUdR on aging are interesting in their own right [6].

Hydrolysis Studies. [1]
(a) Enzymatic Stability [1]
Confluent Caco-2, Capan-2, and AsPC-1 cells were rinsed twice with saline. The cells were washed with 5 mL of pH 7.4 phosphate buffer (10 mmol/L), lysed by ultrasonication, and pelleted by centrifugation for 5 min at 1000g. Protein amount was quantified with Bio-Rad DC Protein Assay using bovine serum albumin as a standard. The protein amount was adjusted to 500 μg/mL, and the hydrolysis reactions were carried out in 96-well plates. Caco-2, AsPC-1, and Capan-2 cell suspensions (250 μL) were placed in triplicate wells, the reactions started with the addition of substrate, and cells were incubated at 37 °C for 120 min. At the desired time point, sample aliquots (35 μL) were removed and added to 150 μL of acetonitrile (ACN) containing 0.1% TFA. The mixtures were filtered with a 0.45 μm filter at 1000g for 10 min at 4 °C. The filtrate was then analyzed via reverse-phase HPLC.

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(b) Stability in Human Plasma [1]
The stability of the prodrugs in human plasma was determined using the procedure below. Undiluted plasma (250 μL) was added to each well in triplicate, and substrate was added to initiate the reactions that were conducted at 37 °C for 2 h. At various time points, aliquots (35 μL) were removed and added to 150 μL of ACN containing 0.1% TFA. The mixtures were filtered with a 0.45 μm filter at 1000g for 10 min at 4 °C. The filtrate was then analyzed via reverse-phase HPLC.

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(c) Chemical Stability [1]
The nonenzymatic hydrolysis of the prodrugs was determined as described above, except that each well contained pH 7.4 phosphate buffer (10 mmol/L) instead of cell homogenate or human plasma.

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(d) Resistance to Metabolism of Floxuridine (FUDR) and Its Prodrugs by Thymidine Phosphorylase [1]
The stability of floxuridine and its prodrugs in the presence of thymidine phosphorylase (TP) was assessed by incubating the desired substrates (200 μM) with TP (2.0 ng/μL) in phosphate buffer (pH 7.0) at 37 °C. Aliquots of the incubation mixture were sampled at 0, 1, 3, 5, 10, 30, 60, and 120 min, and quenched with cold acetonitrile (ACN) with 0.1% TFA, filtered through a 0.45 μm membrane, and analyzed for the concentrations of prodrug, floxuridine, and 5-FU by HPLC.

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[3H]Gly-Sar Uptake Inhibition [1]
Caco-2 cells at nine days postseeding, and AsPC-1 and Capan-2 cells, both at four days postseeding, were incubated with 10 μmol/L Gly-Sar (9.98 μmol/L Gly-Sar and 0.02 μmol/L [3H]Gly-Sar) along with various prodrug concentrations (5−0.05 mmol/L) for 30 min. The cells were washed three times with ice-cold PBS and solubilized with 10 mL of scintillation cocktail, and the amount of cell-associated radioactivity was determined by scintillation counting. IC50 values were determined using nonlinear data fitting (GraphPad Prism version 3.0).

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Transport Studies [1]
Caco-2 cell monolayers were grown on collagen-coated polytetrafluoroethylene membranes for 21 to 24 days, and Capan-2 cell monolayers were grown on the same type of membrane for 14 days. Transepithelial electrical resistance (TEER) was monitored, and values of 240−280 Ω/cm2 in Caco-2 and 380−420 Ω/cm2 in Capan-2 (total area for both cells was 4.67 cm2) were used in the study. Apical side and basolateral sides of transwell inserts were washed with MES (pH 6.0) and HEPES (pH 7.4), respectively. Fresh MES and HEPES buffers were reapplied to transwell inserts and incubated at 37 °C for 15 min. Freshly prepared 0.1 mM drug solution in MES buffer (total 1.5 mL) was placed in the donor chamber, and the receiver chamber was filled with HEPES buffer (total 2.5 mL) Sampling from the receiver chamber (200 μL) was conducted up to a period of 2 h at time intervals of 15, 30, 45, 60, 75, 90, and 120 min, at 37 °C and replaced with an equal volume of fresh HEPES buffer to maintain sink conditions in the receiver chamber. All samples were immediately acidified with 0.1% TFA and analyzed by reverse-phase HPLC.

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Amino acid ester prodrugs of antiviral and anticancer nucleoside drugs were developed to improve oral bioavailability or to reduce systemic toxicity. Researchers studied the interaction of human concentrative nucleoside transporter (hCNT2) cloned from intestine with various amino acid ester prodrugs of Floxuridine (FUdR) and 5,6-dichloro-2-bromo-1-beta-D-ribofuranosylbenzimidazole (BDCRB). Na(+)-dependent uptakes of [(3)H]-inosine and [(3)H]-adenosine were measured in U251 cells transiently expressing intestinal hCNT2. FUdR significantly inhibited the uptake of both [(3)H]-inosine and [(3)H]-adenosine (60-70% of control), while its amino acid ester prodrugs including Val, Phe, Pro, Asp, and Lys esters exhibited markedly decreased inhibition potency (10-30% of control). On the other hand, BDCRB and its amino acid prodrugs markedly inhibited the uptake of both [(3)H]-inosine and [(3)H]-adenosine. Val, Phe, and Pro ester prodrugs of BDCRB showed similar inhibition capacities as parent compound BDCRB (80-90% for adenosine and 60-80% for inosine). The amino acid site of attachment (3'- and 5'-monoesters) and stereochemistry (L- and D-amino acid esters), did not significantly affect the uptake of [(3)H]-inosine and [(3)H]-adenosine. These results demonstrate that the hCNT2 favorably interacts with BDCRB and its amino acid prodrugs, compared to those of FUdR, and that neutral amino acid esters of BDCRB have a high affinity toward this transporter. Therefore, the intestinal hCNT2 may be a target transporter as a factor for modulating oral pharmacokinetics of BDCRB prodrugs [3].

Cell Line: Ovarian cancer cells
Concentration: 0-25 μM
Incubation Time: 4, 8, 24 hours
Result: Was potentiated the sensitivity by PARP inhibitors.

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Cell Proliferation Assays [1]
Cell proliferation studies were conducted with AsPC-1 and Capan-2 cell lines. The cells were seeded onto 96-well plates at 125,000 cells per well and allowed to attach/grow for 24 h before drug solutions were added. The culture medium (RPMI-1640 + 10% fetal bovine serum) was removed, and the cells were gently washed once with sterile pH 6.0 uptake buffer. Floxuridine (FUDR) and floxuridine prodrugs were 2-fold serially diluted in pH 6.0 uptake buffer from 4 to 0.25 mmol/L. Buffer alone was used as 100% viability control. The wash buffer was removed, and 25 μL of drug solution per well was added and incubated at 37 °C for 2 h with AsPC-1 cells and 4 h with Capan-2 cells in the cell incubator. After this time period, the drug solutions were removed and the cells were gently washed twice with sterile uptake buffer. Fresh culture medium was then added to each well after washing, and the cells were allowed to recover for 24 h before evaluating cell viability via 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt (XTT) assays. A mixture (30 μL) containing XTT (1 mg/mL) in sterile RPMI-1640 without phenol red and phenazine methosulfate (N-methyl dibenzopyrazine methyl sulfate in sterile PBS, 0.383 mg/mL) reagents was added to the cells and incubated at 37 °C for 1 h, after which the absorbance at 450 nm was read. GI50 values were calculated using GraphPad Prism version 3.0 by nonlinear data fitting.

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The inhibitory effects of leucovorin (LV) combined with 5-fluorouracil (FUra) or Floxuridine (FUDR) (FdUrd) on growth of human T-lymphoblast leukemia cells (CCRF-CEM) were determined as a function of time, dose, and sequence of exposure. Exposure of CCRF-CEM cells in exponential growth to LV (1-100 microM) for 4 hours and to FUra (100 microM) or FdUrd (0.5 microM) during the last 2 hours resulted in synergistic inhibitory effects on cell growth. Synergism was dependent on LV dose (100 greater than 10 greater than 1 microM) and did not occur at 0.1 microM. No clear dependence of synergy on sequence was observed with FUra and LV combinations. With LV and FdUrd combinations, synergism was dependent on sequence of exposure (LV + FdUrd and LV----FdUrd were synergistic, but FdUrd----LV was not). Thymidine (0.1 microM), added after drug treatment, substantially rescued CCRF-CEM cells from LV----FUra cytotoxicity. Concomitant hypoxanthine (100 microM) only partially protected CCRF-CEM cells from the toxicity of this combination. These results are consistent with the hypothesis that the mechanism by which LV potentiates fluoropyrimidine cytotoxicity is the enhancement of complex formation between thymidylate synthase and 5-fluorodeoxyuridylate, presumably as a consequence of an increase of intracellular levels of 5,10-methylenetetrahydrofolate generated from LV. Also, enhanced stability of this complex in the presence of high levels of the folate coenzyme may contribute to the synergy observed. These data also provide a rationale for use of FUra and especially FdUrd and LV in the treatment of lymphoid malignancies in man.[2]

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Proliferating human Tenon's capsule fibroblasts were exposed for 5 minutes to a wide range of concentrations of fluorouracil, Floxuridine (FUDR), and mitomycin. High concentrations of all three agents had prolonged effects on cell proliferation and morphologic characteristics compared with untreated control cells up to 36 days. The highest concentrations of both floxuridine (15,000 micrograms/mL) and mitomycin (1000 micrograms/mL) had an apparent cidal effect, reducing cell numbers below initial cell density. In contrast, although the highest concentration of fluorouracil (25,000 micrograms/mL) inhibited cell proliferation by more than 50% relative to the untreated control cells at 36 days, the cell numbers still increased fourfold compared with the initial cell density. These results demonstrate that 5-minute treatments with high concentrations of these drugs have prolonged effects on the proliferation of human Tenon's capsule fibroblasts in vitro. Single-dose regimens using high concentrations of these drugs at the time of operation may achieve results similar to those of protocols that involve repeated applications[4].

C57BL/6 mice injected with S. aureus
0.5-1.25 mg/kg
once per day for 7 days or single dose

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To examine the effects of Floxuridine (FUDR) on worms, drug was added topically onto a 2-day old bacterial lawn to a final concentration of 50 μM. Worms were transferred from untreated NGM plates at L4, or day 1, day 2 or day 3 of adulthood. [6]
Lifespan assays[6]
Gravid adults were cultured on fresh NGM plates to lay eggs, and two days later L4 larvae were picked to new plates for lifespan measurements. Trials were conducted at 20 °C for N2 strains. Temperature sensitive sterile glp-4(bn2) mutants were cultured at 15 °C until L4 and then transferred to 25 °C. Nematodes were transferred daily during the reproductive period to avoid confusion with progeny. Population cohorts were scored for mortality every other day until the death of the last worm. Deaths due to internal hatching of larvae or rupture were censored. The L4 stage was recorded as day 0 for the trials.

Absorption, Distribution and Excretion
Floxuridine can be excreted as unchanged drug, urea, fluorouracil, a-fluoro-bureidopropionic acid, dihydrofluorouracil, a-fluoro-b-guanidopropionic acid and a-fluoro-b-alanine via the kidneys. Floxuridine may also be excreted as respiratory carbon dioxide.
... Floxuridine /is/ ... administered parenterally, since absorption after ingestion ... is unpredictable and incomplete.
It is not known whether floxuridine is distributed into milk.
Some /Floxuridine/ crosses the blood-brain barrier; active metabolites are localized intracellularly.
Elimination /is/ respiratory (as carbon dioxide), about 60%. Renal /elimination accounts for/ 10 to 13% (as unchanged drug and metabolites).

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Metabolism / Metabolites
Hepatic.
Biotransformation /is/ hepatic and in tissues, extensive, to the monophosphate derivative and fluorouracil; after continuous intra-arterial infusion, conversion to the monophosphate derivative is enhanced; largely converted to fluorouracil after rapid intravenous or intra-arterial injection.
Following infusion of small doses of floxuridine, most of the drug appears to be anabolized to FUDR-MP, the active metabolite of the drug. When single doses are administered rapidly, floxuridine is apparently rapidly catabolized to fluorouracil.
Floxuridine and fluorouracil are metabolized in the liver. Metabolic degradation of floxuridine is less when the drug is given by continuous infusion than when given by single injections. The drug is excreted intact and as urea, fluorouracil, a-fluoro-ß-ureidopropionic acid, dihydrofluorouracil, alpha-fluoro-beta-guanidopropionic acid, and alpha-fluoro-beta-alanine in the urine and as respiratory carbon dioxide.
Metabolic degradation occurs, particularly in the liver. Floxuridine is converted by thymidine or deoxyuridine phosphorylases into 5-fluorouracil. 5-Fluorouracil is inactivated by reduction of the pyrimidine ring; this reaction is carried out by dihydrouracil dehydrogenase, which is found in liver, intestinal mucosa, and other tissues. Inherited deficiency of this enzyme leads to greatly increased sensitivity to the drug. The product of this reaction, 5-fluoro-5,6-dihydrouracil is ultimately degraded to alpha-fluoro-beta-alanine ... .

Hepatotoxicity
Serum aminotransferase elevations occur in a high proportion of patients given floxuridine by infusion into the hepatic artery, the reported rates ranging from 25% to 100%. These elevations are generally mild to moderate in severity and resolve with stopping therapy. "Chemical hepatitis," however, not infrequently is a cause of dose modification or delay in cycles of treatment. In addition, prolonged or repeated hepatic arterial infusions of FUDR can cause acalculous cholecystitis and multiple biliary strictures that can cause jaundice and a chronic sclerosing cholangitis-like syndrome. Between 5% and 25% of patients treated with hepatic arterial infusions of FUDR will develop symptomatic biliary strictures with pain and jaundice. These typically arise after 2 to 6 months of therapy, but can appear later, even more than a year after initiating FUDR therapy. The biliary strictures typically affect central bile ducts in the area of the porta hepatis, generally in and around the bifurcation of the common hepatic duct. Similar inflammation and fibrosis account for the acalculous cholecystitis that can occur with FUDR therapy, but which can be avoided by cholecystectomy at the time of hepatic resection of metastases or placement of the intraarterial infusion pump. The biliary strictures generally improve with stopping therapy, but can progress or require endoscopic or surgical intervention. Deaths from progressive biliary strictures and cholestatic liver injury have been described and can be a major cause of death among survivors of this metastatic tumor. The frequency of biliary strictures after FUDR therapy may be decreased by concurrent administration of dexamethasone and avoided by monitoring with hepatic and biliary imaging. However, the many complications of hepatic arterial infusion chemotherapy have decreased enthusiasm for this therapy, particularly with newer, more potent systemic antineoplastic agents.
Likelihood score: A (well known cause of clinically apparent liver and biliary injury).

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Interactions
Leukopenic and/or thrombocytopenic effects of floxuridine may be increased with concurrent or recent therapy /with blood dyscrasia-causing medications/ if these medications cause the same effects; dosage adjustment of floxuridine, if necessary, should be based on blood counts.
Additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively /with floxuridine/.
Because normal defense mechanisms may be suppressed by floxuridine therapy, the patients antibody response to killed virus vaccines may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patients ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year.
Because normal defense mechanisms may be suppressed by floxuridine therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patients antibody repose to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematological status and only with the knowledge and consent of the physician managing the floxuridine therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patients ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Immunization with oral poliovirus vaccine should also be postponed in persons in close contact with the patient, especially family members.

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Toxicity of HAI FUDR [5]
The toxicity of HAI can be mechanical, chemical, or a combination of both. Surgically implantable pumps have low complication rates. Allen and colleagues reported on HAI pump complications in 544 patients throughout the course of treatment. Complications within the first 30 days of placement were more likely to be catheter occlusions or arterial thromboses and less likely to be salvaged. Overall rates of pump failure were low being 9% at 1 year and 16% at 2 years. The overall pump complication rate was 22%, and the majority of these complications were salvaged with 80% remaining functional for at least 2 years. All patients have a nuclear medicine macro-aggregated albumin scan before the pump is used to assess whether the liver is being perfused or if there is extrahepatic perfusion via side branches of the gastroduodenal artery. If there is misperfusion to the stomach or duodenum, ulceration or diarrhea can result. In contrast to systemic chemotherapy, myelosuppression, nausea, and vomiting do not occur with HAI FUDR. Hepatotoxicity from HAI depends on the drugs being used and the duration of treatment. The hepatic artery supplies the bile ducts, and therefore toxicity of HAI FUDR can be biliary. Elevation in liver enzymes or bilirubin is the most common toxicity associated with HAI therapy, occurring in 42% of patients in the randomized trials for unresectable liver disease reported above. Increase in transaminase levels is not uncommon (up to 70% of cases) and can be an early sign of biliary damage. Increases in bilirubin and alkaline phosphatase are more serious. Up to 29% of cases before the addition of Dex to the pump developed strictures of the bile ducts (biliary sclerosis) (ref. 38). In the adjuvant pump studies at our institution, a larger than twofold increase in alkaline phosphatase was seen in 27% to 43% of cases. An increase in bilirubin greater than 3.0 mg/dL was seen in 6% to 19% of cases with biliary stents required in 3% to 8% of cases. Transaminases increased by 37% to 59%. In the recently updated study by Kemeny and colleagues, HAI FUDR/Dex was combined with oxaliplatin and irinotecan over a 5-week cycle. Toxicities during the first two cycles were: grade 3 diarrhea (33%), grade 3/4 alkaline phosphatase (15% and 11%, respectively), grade 3/4 AST (19%), grade 3 bilirubin (4%), and grade 3/4 neutropenia (19% and 4%, respectively). Late toxicity (after the first two cycles) included grade 3 diarrhea (7%), grade 3 or 4 alkaline phosphatase (22% and 11%, respectively), grade 3/4 AST (7%), grade 3/4 neutropenia (15% and 11%, respectively), and neurotoxicity (19%). Thus an algorithm for dose reductions based on liver blood tests has been devised, and FUDR can be dose adjusted accordingly (see Table 3). As mentioned above, the addition of Dex to FUDR reduces biliary toxicity. HAI FUDR/Dex is administered every month (if enzymes are normal). The pump continuously infuses drug, and after 2 weeks the reservoir is emptied and then refilled with heparin saline or glycerol, which then infuses over a further 2 weeks. If a patient develops an elevated bilirubin, chemotherapy is held, and Dex with heparinized saline is placed in the pump. If the bilirubin still does not normalize, then an ERCP can be done to evaluate for focal strictures that may respond to dilatation. When the pump is not in use, glycerol is inserted every 6 to 8 weeks to keep the catheter patent. If the pump is no longer required it can be surgically removed by a small incision and the catheter in the hepatic artery is cut off from the pump and left in place.

[1]. Mol Pharm. 2008 Sep-Oct;5(5):717-27.

[2]. Cancer Treat Rep. 1987 Apr;71(4):381-9.

[3]. Biol Pharm Bull. 2006 Feb;29(2):247-52.

[4]. Arch Ophthalmol. 1992 Aug;110(8):1150-4.

[5]. Mol Cancer Ther. 2009 May;8(5):1015-25.

[6]. Biochem Biophys Res Commun. 2019 Feb 12;509(3):694-699.

Therapeutic Uses
Antimetabolites, Antineoplastic; Antiviral Agents
Floxuridine, given by continuous regional intra-arterial infusion, is indicated for palliative management of colorectal carcinoma metastatic to the liver that has not responded to other treatment. Floxuridine is most useful when the disease has not extended beyond an area capable of infusion via a single artery. /Included in US product labeling/
Floxuridine also is indicated for carcinoma of the ovary and kidney not responsive to other antimetabolites. /Not Include in the US product label/
Floxuridine has also been used for carcinoma of the breast, ovary, cervix, urinary bladder, kidney, and prostate not responsive to other antimetabolites. /NOT included in US product labeling/

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Drug Warnings
Floxuridine is metabolized to fluorouracil, but the full spectrum of fluorouracil toxicity is not expected with floxuridine because of regional administration of the drug by intra-arterial infusion. However, the possibility of typical adverse effects of fluorouracil during floxuridine therapy should be considered.
Nausea, vomiting, and diarrhea are common adverse effects; anorexia, cramps, and pain also may occur. Stomatitis is one of the most common signs of specific toxicity. Enteritis occurs frequently and duodenal ulcer, duodenitis, gastritis, gastroenteritis, glossitis, GI bleeding, and pharyngitis also have been reported.
Leukopenia and anemia occur commonly with floxuridine therapy; thrombocytopenia also may occur. The patient's hematologic status must be carefully monitored.
Pancytopenia and agranulocytosis have been reported in patients receiving fluorouracil; because of its pharmacologic similarity, these adverse hematologic effects might occur in patients receiving floxuridine.
For more Drug Warnings (Complete) data for FLOXURIDINE (25 total), please visit the HSDB record page.

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Pharmacodynamics
Floxuridine is an anti-metabolite or a pyrimidine analog that works by disrupting the process S-phase of cell division, selectively targeting rapidly dividing cells. Due to the structural similarities, antimetabolites act as pyrimidine-like molecules and prevent normal pyrimidines from being incorporated into DNA. After successful biotransformation, floxuridine is converted into an active component, flurouracil, which blocks the enzyme which converts cytosine nucleosides into the deoxy derivative. Flurouracil also physically prevents the incorporation of thymidine nucleotides into the DNA strand by taking their place, further preventing DNA synthesis.

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Dipeptide monoester prodrugs of floxuridine were synthesized, and their chemical stability in buffers, resistance to glycosidic bond metabolism, affinity for PEPT1, enzymatic activation and permeability in cancer cells were determined and compared to those of mono amino acid monoester floxuridine prodrugs. Prodrugs containing glycyl moieties were the least stable in pH 7.4 buffer ( t 1/2 < 100 min). The activation of all floxuridine prodrugs was 2- to 30-fold faster in cell homogenates than their hydrolysis in buffer, suggesting enzymatic action. The enzymatic activation of dipeptide monoester prodrugs containing aromatic promoieties in cell homogenates was 5- to 20-fold slower than that of other dipeptide and most mono amino acid monoester prodrugs ( t 1/2 approximately 40 to 100 min). All prodrugs exhibited enhanced resistance to glycosidic bond metabolism by thymidine phosphorylase compared to parent floxuridine. In general, the 5'-O-dipeptide monoester floxuridine prodrugs exhibited higher affinity for PEPT1 than the corresponding 5'-O-mono amino acid ester prodrugs. The permeability of dipeptide monoester prodrugs across Caco-2 and Capan-2 monolayers was 2- to 4-fold higher than the corresponding mono amino acid ester prodrug. Cell proliferation assays in AsPC-1 and Capan-2 pancreatic ductal cell lines indicated that the dipeptide monoester prodrugs were equally as potent as mono amino acid prodrugs. The transport and enzymatic profiles of 5'- l-phenylalanyl- l-tyrosyl-floxuridine, 5'- l-phenylalanyl- l-glycyl-floxuridine, and 5'- l-isoleucyl- l-glycyl-floxuridine suggest their potential for increased oral uptake, delayed enzymatic bioconversion and enhanced resistance to metabolism to 5-fluorouracil, as well as enhanced uptake and cytotoxic activity in cancer cells, attributes that would facilitate prolonged systemic circulation for enhanced therapeutic action. [1] Floxuridine is a pyrimidine 2'-deoxyribonucleoside compound having 5-fluorouracil as the nucleobase; used to treat hepatic metastases of gastrointestinal adenocarcinomas and for palliation in malignant neoplasms of the liver and gastrointestinal tract. It has a role as an antineoplastic agent, an antimetabolite, an antiviral drug and a radiosensitizing agent. It is a pyrimidine 2'-deoxyribonucleoside, an organofluorine compound and a nucleoside analogue.

An antineoplastic antimetabolite that is metabolized to fluorouracil when administered by rapid injection. Floxuridine is available as a sterile, nonpyrogenic, lyophilized powder for reconstitution. When administered by slow, continuous, intra-arterial infusion, it is converted to floxuridine monophosphate. It has been used to treat hepatic metastases of gastrointestinal adenocarcinomas and for palliation in malignant neoplasms of the liver and gastrointestinal tract.

Floxuridine is an Antimetabolite.
Floxuridine (FUDR) is a pyrimidine analogue used as an antineoplastic agent, usually as a continuous hepatic arterial infusion to treat hepatic metastases from colon cancer. Intraarterial floxuridine is associated with a very high rate of serum enzyme and bilirubin elevations during therapy, and with frequent biliary damage that can result in a secondary sclerosing cholangitis, which can be severe and lead to cirrhosis.

Floxuridine is a fluorinated pyrimidine monophosphate analogue of 5-fluoro-2'-deoxyuridine-5'-phosphate (FUDR-MP) with antineoplastic activity. As an antimetabolite, floxuridine inhibits thymidylate synthase, resulting in disruption of DNA synthesis and cytotoxicity. This agent is also metabolized to fluorouracil and other metabolites that can be incorporated into RNA and inhibit the utilization of preformed uracil in RNA synthesis. (NCI04)

FLOXURIDINE is a small molecule drug with a maximum clinical trial phase of IV (across all indications) that was first approved in 1970 and is indicated for cancer and neoplasm and has 17 investigational indications. This drug has a black box warning from the FDA.

An antineoplastic antimetabolite that is metabolized to fluorouracil when administered by rapid injection; when administered by slow, continuous, intra-arterial infusion, it is converted to floxuridine monophosphate. It has been used to treat hepatic metastases of gastrointestinal adenocarcinomas and for palliation in malignant neoplasms of the liver and gastrointestinal tract.

C9H11FN2O5

246.19

246.065

C, 43.91; H, 4.50; F, 7.72; N, 11.38; O, 32.49

50-91-9

5790

White powder

1.8±0.1 g/cm3

483.0±55.0 °C at 760 mmHg

148 °C(lit.)

245.9±31.5 °C

0.0±2.8 mmHg at 25°C

1.676

-1.22

3

6

2

17

386

3

FC1C(N([H])C(N(C=1[H])[C@@]1([H])C([H])([H])[C@@]([H])([C@@]([H])(C([H])([H])O[H])O1)O[H])=O)=O

ODKNJVUHOIMIIZ-RRKCRQDMSA-N

InChI=1S/C9H11FN2O5/c10-4-2-12(9(16)11-8(4)15)7-1-5(14)6(3-13)17-7/h2,5-7,13-14H,1,3H2,(H,11,15,16)/t5-,6+,7+/m0/s1

5-fluoro-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.08 mg/mL (8.45 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (8.45 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (8.45 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 100 mg/mL (406.19 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)