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.
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 humanpancreatic cancer lines, there was additivity for the imexon/GEM combination. There was significantly greater efficacy for the drug combination in Panc-1xenograft 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.
Authors: Malcolm J Moore; David Goldstein; John Hamm; Arie Figer; Joel R Hecht; Steven Gallinger; Heather J Au; Pawel Murawa; David Walde; Robert A Wolff; Daniel Campos; Robert Lim; Keyue Ding; Gary Clark; Theodora Voskoglou-Nomikos; Mieke Ptasynski; Wendy Parulekar Journal: J Clin Oncol Date: 2007-04-23 Impact factor: 44.544
Authors: Steven J Cohen; Mark M Zalupski; Manuel R Modiano; Paul Conkling; Yehuda Z Patt; Peg Davis; Robert T Dorr; Michelle L Boytim; Evan M Hersh Journal: Cancer Chemother Pharmacol Date: 2009-10-24 Impact factor: 3.333
Authors: Richard Herrmann; György Bodoky; Thomas Ruhstaller; Bengt Glimelius; Emilio Bajetta; Johannes Schüller; Piercarlo Saletti; Jean Bauer; Arie Figer; Bernhard Pestalozzi; Claus-Henning Köhne; Walter Mingrone; Salomon M Stemmer; Karin Tàmas; Gabriela V Kornek; Dieter Koeberle; Susanne Cina; Jürg Bernhard; Daniel Dietrich; Werner Scheithauer Journal: J Clin Oncol Date: 2007-06-01 Impact factor: 44.544
Authors: Elena V Sheveleva; Terry H Landowski; Betty K Samulitis; Geoffrey Bartholomeusz; Garth Powis; Robert T Dorr Journal: Mol Cancer Res Date: 2012-01-24 Impact factor: 5.852