Imexon enhances gemcitabine cytotoxicity by inhibition of ribonucleotide reductase

Nicholas O. Roman, Betty K. Samulitis, Lee Wisner, Terry H. Landowski, Robert T. Dorr

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Purpose: Gemcitabine (GEM) is currently the standard first line treatment for pancreatic cancer; however, the overall survival of patients with this disease remains poor. Imexon is a pro-oxidant small molecule which produced a high response rate in combination with GEM in a phase I trial in pancreatic cancer. In this study, we investigate the combination of GEM with a novel redox-active agent, imexon, in vitro and in vivo. Methods: Median effect analysis was used for in vitro combination cytotoxicity. The effect of imexon on GEM metabolism and uptake into cells and into DNA and effects on ribonucleotide reductase (RNR) were examined in vitro. The pharmacokinetics and antitumor efficacy of the imexon/GEM combination was evaluated in mouse models. Results: In three human pancreatic cancer lines, there was additivity for the imexon/GEM combination. There was significantly greater efficacy for the drug combination in Panc-1 xenograft tumors. A pharmacokinetic study in mice showed a near doubling in the AUC of imexon when GEM was co-administered, with no effect of imexon on GEM's pharmacokinetic disposition. In vitro, imexon did not alter GEM's metabolism or uptake into DNA, but significantly inhibited RNR, and this effect was greater when combined with GEM. Conclusions: These results suggest that the interaction between imexon and GEM may be due to complimentary inhibition of RNR plus an enhanced exposure to imexon when the GEM is administered in vivo. This combination is currently being tested in a randomized phase II trial in pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)183-192
Number of pages10
JournalCancer Chemotherapy And Pharmacology
Volume67
Issue number1
DOIs
StatePublished - Jan 1 2011

Keywords

  • Gemcitabine
  • Imexon
  • Pancreatic cancer
  • Ribonucleotide reductase
  • Synergy

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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