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 Citations (Scopus)

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 2011

Fingerprint

gemcitabine
Ribonucleotide Reductases
Cytotoxicity
Pancreatic Neoplasms
Pharmacokinetics
Air cushion vehicles
Metabolism
4-imino-1,3-diazabicyclo(3.1.0)hexan-2-one
DNA
Drug Combinations

Keywords

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

ASJC Scopus subject areas

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

Cite this

Imexon enhances gemcitabine cytotoxicity by inhibition of ribonucleotide reductase. / Roman, Nicholas O.; Samulitis, Betty K.; Wisner, Lee; Landowski, Terry H; Dorr, Robert T.

In: Cancer Chemotherapy and Pharmacology, Vol. 67, No. 1, 01.2011, p. 183-192.

Research output: Contribution to journalArticle

@article{5dc54ed08c5f49d6bca2484a8e91ae19,
title = "Imexon enhances gemcitabine cytotoxicity by inhibition of ribonucleotide reductase",
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.",
keywords = "Gemcitabine, Imexon, Pancreatic cancer, Ribonucleotide reductase, Synergy",
author = "Roman, {Nicholas O.} and Samulitis, {Betty K.} and Lee Wisner and Landowski, {Terry H} and Dorr, {Robert T}",
year = "2011",
month = "1",
doi = "10.1007/s00280-010-1306-0",
language = "English (US)",
volume = "67",
pages = "183--192",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "1",

}

TY - JOUR

T1 - Imexon enhances gemcitabine cytotoxicity by inhibition of ribonucleotide reductase

AU - Roman, Nicholas O.

AU - Samulitis, Betty K.

AU - Wisner, Lee

AU - Landowski, Terry H

AU - Dorr, Robert T

PY - 2011/1

Y1 - 2011/1

N2 - 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.

AB - 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.

KW - Gemcitabine

KW - Imexon

KW - Pancreatic cancer

KW - Ribonucleotide reductase

KW - Synergy

UR - http://www.scopus.com/inward/record.url?scp=78651094422&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78651094422&partnerID=8YFLogxK

U2 - 10.1007/s00280-010-1306-0

DO - 10.1007/s00280-010-1306-0

M3 - Article

C2 - 20339847

AN - SCOPUS:78651094422

VL - 67

SP - 183

EP - 192

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 1

ER -