Title
Melphalan antitumor efficacy and hepatotoxicity: The effect of variable infusion duration in the hepatic artery
Author
Rothbarth, J.
Woutersen, R.A.
Sparidans, R.W.
van de Velde, C.J.H.
Mulder, G.J.
Publication year
2003
Abstract
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 μmol), 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 μmol 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.
Subject
Toxicology
Toxicology and Applied Pharmacology
melphalan
animal cell
animal experiment
animal model
animal tissue
antineoplastic activity
article
biliary tract fibrosis
body weight
colon tumor
controlled study
drug efficacy
drug infusion
drug liver level
drug tumor level
hepatic artery
high performance liquid chromatography
liver metastasis
liver perfusion
liver toxicity
nonhuman
priority journal
rat
Animals
Antineoplastic Agents, Alkylating
Disease Models, Animal
Hepatic Artery
Infusions, Intra-Arterial
Liver Neoplasms
Male
Melphalan
Neoplasm Transplantation
Rats
Treatment Outcome
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DOI
https://doi.org/10.1124/jpet.103.049379
TNO identifier
237133
ISSN
0022-3565
Source
Journal of Pharmacology and Experimental Therapeutics, 305 (3), 1098-1103
Document type
article