Biliary sclerosis in patients receiving hepatic arterial infusions of floxuridine.

Höhn, D.; Melnick, Jane; Stagg, Robert; Altman, David A.; Friedman, Michael; Ignoffo, Robert J.; Ferrell, Linda D.; Lewis, Brian J.

doi:10.1200/jco.1985.3.1.98

Cited by 157 publications

(47 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Treatment of hepatic tumors with regional infusion of fluoropyrimidines has been shown to produce a high response rate (15). However, therapy has been limited by the frequent development of cholestasis that is associated with this treatment (16,17). The cholestasis does not arise from hepatocellular toxicity but appears to result from specific damage to the bile ducts of these patients.…”

Section: Discussionmentioning

confidence: 99%

Metabolism of 5-fluorouracil to an N-cholyl-2-fluoro-beta-alanine conjugate: previously unrecognized role for bile acids in drug conjugation.

Sweeny¹,

Barnes²,

Heggie³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Recently we demonstrated clinically significant levels of a previously unrecognized metabolite of the anticancer drug 5-fluorouracil (FUra) in bile ofcancer patients. In the present study, reanalysis of bile from these patients demonstrated the presence of not one but two previously unrecognized metabolites. The major unrecognized metabolite was purified by reversed-phase HPLC, after which its molecular weight was determined by fast-atom-bombardment mass spectrometry to be 497. The similarity in HPLC retention times and molecular weights of this FUra derivative and the bile acids N-cholylglycine (Mr 465) and N-cholyltaurine (Mr 515), along with the structural similarity of the FUra catabolite 2-fluoro-,B-alanine and the amino acids glycine and taurine, led to the hypothesis that this metabolite could be a conjugate of 2-fluoro-,B-alanine and cholic acid. This hypothesis was tested and confirmed by hydrolyzing the purified metabolite by cholylglycine hydrolase after which: (i) 2-fluoro-,-alanine was demonstrated by using a sensitive HPLC technique capable of resolving all of the known putative FUra metabolites, and (ii) unconjugated cholic acid was identified by both GC and GC-MS. Additionally, chemically synthesized N-cholyl-2-fluoro-8-alanine was shown to cochromatograph on HPLC and TLC with the purified biiary metabolite. In summary, this study demonstrates a unique, so far as we know, pathway of drug metabolism in man in which an amino acid drug metabolite is conjugated with cholic acid and eliminated into the bile.Furthermore, the finding that 2-fluoro-p-alanine is conjugated to bile acids may provide some insight Into the mechanism of cholestasis that is frequently observed after administration of fluoropyrimidine by hepatic arterial infusion.Although first synthesized 30 years ago, fluoropyrimidines are still widely used in the treatment of a variety of cancers.The anabolism of the fluoropyrimidines to cytotoxic nucleotides has been extensively examined (1, 2) and appears to be responsible for the chemotherapeutic action of these agents. On the other hand, relatively few studies have focused on fluoropyrimidine catabolism. This is despite the fact that >80% of the administered dose is metabolized via the catabolic route (3). Additionally, inadequacies in the analytical techniques previously used for the separation of fluoropyrimidine catabolites has until recently prevented a comprehensive examination of the catabolism of these agents. However, these technical problems have been overcome by the development of a specific HPLC method for the separation of all of the putative fluoropyrimidine metabolites (4).Our laboratory has demonstrated the formation of a 5-fluorouracil (FUra) glucuronide conjugate in isolated rat hepatocytes (5) and the presence of an unidentified FUra metabolite in bile of cancer patients (6). In the present study, further analysis of bile from these patients has shown the presence of two previously unrecognized FUra metabolites. These metabolites did not appear to represent FUra...

show abstract

Section: Discussionmentioning

confidence: 99%

Metabolism of 5-fluorouracil to an N-cholyl-2-fluoro-beta-alanine conjugate: previously unrecognized role for bile acids in drug conjugation.

Sweeny¹,

Barnes²,

Heggie³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…When the 5-FU metabolite fluorodeoxyuridine (FUDR, floxuridine) is given intra-arterially by implantable pump for hepatic metastases from colorectal carcinoma, new toxicities become apparent [42]. There are two major pictures:…”

Section: Antimetabolitesmentioning

confidence: 99%

Hepatotoxicity of Chemotherapy

2001

View full text Add to dashboard Cite

After assessment of tumor histology, the next important factor to consider in the selection of a chemotherapy regime is organ function. Patients who are to receive chemotherapy require careful assessment of liver function prior to treatment to determine which drugs may not be appropriate, and which drug doses should be modified. Following therapy abnormalities of liver function tests may be due to the therapy rather than to progressive disease, and this distinction is of critical importance. Furthermore, not all abnormalities in liver function are due to the tumor or its treatment, and other processes, such as hepatitis, must be kept in mind. This article reviews the hepatic toxicity of chemotherapeutic agents, and suggests dose modifications based upon liver function abnormalities. Emphasis is placed on agents known to be hepatotoxic, and those agents with hepatic metabolism.

show abstract

“…Unfortunately, the group of rats treated with 5-min HAI with melphalan experienced major hepatobiliary toxicity. Histochemical examination showed cholangiofibrosis in the liver of our rats, which histopathologically is similar to biliary sclerosis in humans, a well known complication of arterially infused fluorodeoxyuridine (Hohn et al, 1985;Kemeny et al, 1992;Rougier et al, 1992;Lorenz and Muller, 2000).…”

Section: Discussionmentioning

confidence: 81%

Melphalan Antitumor Efficacy and Hepatotoxicity: The Effect of Variable Infusion Duration in the Hepatic Artery

Rothbarth

Woutersen²,

Sparidans³

et al. 2003

J Pharmacol Exp Ther

View full text Add to dashboard Cite

The optimum conditions (duration and concentration) of a fixed dose, intra-arterial melphalan infusion in relation to its antitumor effect and toxicity in the liver were investigated in a rat colon tumor model (CC531) of liver metastases. We studied the difference in tumor and liver uptake, as well as antitumor effect and hepatotoxicity after 5-and 20-min hepatic arterial infusion (HAI) of a fixed melphalan dose. Melphalan content in perfusate, liver, and tumor tissue was analyzed by high-performance liquid chromatography. The antitumor effect and hepatotoxicity in rats treated either systemically or with 5-and 20-min HAI, with a fixed dose melphalan (4.4 mol), were assessed 2 weeks after treatment. No difference in melphalan content of tumor/ liver tissue or antitumor effect was observed between rats treated with 5-and 20-min HAI. Hepatotoxicity was strongly affected by perfusion duration/concentration, however. Rats treated with 5-min HAI weighed significantly less, and liver toxicity parameters were significantly increased compared with those of all other groups; eight of nine rats showed severe cholangiofibrosis. Body weights and liver toxicity parameters of the rats treated with 20-min HAI were not statistically different from the control group. In conclusion, duration of HAI with 4.4 mol of fixed dose melphalan did not affect tumor uptake and antitumor effect, but the resulting increase in melphalan concentration had major impact on hepatobiliary toxicity. Therefore, in a clinical setting, caution should be taken when infusion duration and concentration of melphalan are changed.Chemotherapeutic treatment is the therapy of choice when curative resection of liver metastases is not possible, for instance because too many metastases are present or the localization or size of these metastases precludes total resection. In the treatment of liver tumors, hepatic artery infusion (HAI) of cytostatics is favored because liver tumors are mainly vascularized by the hepatic artery (Breedis and

show abstract

Biliary sclerosis in patients receiving hepatic arterial infusions of floxuridine.

Cited by 157 publications

References 6 publications

Metabolism of 5-fluorouracil to an N-cholyl-2-fluoro-beta-alanine conjugate: previously unrecognized role for bile acids in drug conjugation.

Metabolism of 5-fluorouracil to an N-cholyl-2-fluoro-beta-alanine conjugate: previously unrecognized role for bile acids in drug conjugation.

Hepatotoxicity of Chemotherapy

Melphalan Antitumor Efficacy and Hepatotoxicity: The Effect of Variable Infusion Duration in the Hepatic Artery

Contact Info

Product

Resources

About