Amifostine (Ethyol) as modulator of hepatic and biliary toxicity from intraarterial hepatic chemoembolization: Results of a phase I study

G. Fiorentini, P. Giovanis, M. Leoni, U. De Giorgi, A. Cariello, C. Dazzi, A. Caldeo

Research output: Contribution to journalArticle

Abstract

Background/Aims: Hepatic and biliary toxicity are still significant problems after intraarterial hepatic chemoembolization for liver metastases from large bowel cancers. In about 30-60% of the patients hepatic and biliary toxicity are the limiting aspects of intraarterial hepatic chemoembolization and exclude a lot of patients from a repeated beneficial treatment. Amifostine (Ethyol) is a prodrug that must be dephosphorylated to the free thiol in which form it can detoxify free oxygen radicals generated by radiation, hypoxia and by drugs such anthracyclines, platinum analogues and alkylating agents. Amifostine as inactive prodrug is primarily metabolized at the tissue site by membrane alkaline phosphatase, which is highly active in the cell membranes of normal endothelial cells and biliary tree cells but not in the cell membranes and neovascular capillaries of tumor. When dephosphorylated to WR-1065, amifostine is rapidly taken up into normal liver cells by a carrier-mediated facilitated diffusion transport process. The resulting high thiol content in normal liver tissue (biliary cells and hepatocytes) compared with the negligible concentration in liver metastases from large bowel cancers probably provides for selective drug resistance to intraarterial hepatic chemoembolization protecting normal tissue and allowing full therapeutic effect on tumor. Methodology: From May 1997 we planned a phase I study in patients receiving intraarterial hepatic chemoembolization for liver metastases from large bowel cancers. We started at 200mg/m2 dissolved in 250cc of normal saline given in 15min in the intrahepatic artery 20min before an intraarterial hepatic chemoembolization consisting of mitomycin 10mg/m2, epirubicin-50, cisplatin-60 diluted in 10 mL of contrast media, mixed in 15mL of lipiodol UF followed by a gelfoam powder solution until stagnation of the flow. The escalating dose, every 3 patients, was: 200mg/m2, 250mg/m2, 300mg/m2, 350mg/m2. Results: Toxicity has been observed at 350mg/m2:1 patient reported transient hypotension (Blood pressure 70/50mm Hg), 1 patient had skin flushing and dyspnoea. 300mg/m2 are well tolerated and seem to reduce the level of transaminases, lactic acid dehydrogenase, and γ-glutamyl transferase. Also the duration of necrotic damage, always observed after intraarterial hepatic chemoembolization, seems shorter compared with historical controls. Conclusions: Amifostine can be certainly administered at 300mg/m2 as intraarterial infusion and could be a significant step to ameliorate the therapeutic ratio of intraarterial hepatic chemoembolization.

Original languageEnglish
Pages (from-to)313-316
Number of pages4
JournalHepato-Gastroenterology
Volume48
Issue number38
Publication statusPublished - 2001

Keywords

  • Amifostine
  • Intraarterial hepatic chemoembolization
  • Toxicity modulator

ASJC Scopus subject areas

  • Gastroenterology

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