Preclinical antitumor activity, pharmacokinetics and pharmacodynamics of imexon in mice

Alan Pourpak, Ross O. Meyers, Betty K. Samulitis, Hsiao-Hui Chow, Carole Y. Kepler, Mary A. Raymond, Evan M Hersh, Robert T Dorr

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Imexon, a novel pro-oxidant, thiol-binding agent, is currently in phase I/II clinical trials in patients with advanced solid tumors. The aim of this study was to characterize the preclinical pharmacology of imexon in vivo. We investigated the anticancer activity of imexon in several cancer cell lines grown as xenografts in severe combined immunodeficient mice. Imexon was active against both hematologic and solid tumor types. The maximally tolerated dose, at the selected dosing schedule, was 150 mg/kg. Using the maximally tolerated dose of imexon, we sought to identify a potential pharmacodynamic biomarker to monitor the mechanistic effect systemically. As imexon binds cellular thiols in vitro, thiol depletion by imexon in vivo was evaluated as a potential biomarker. Following a single 150 mg/kg dose of imexon by intraperitoneal injection, glutathione levels decreased by 40% at 3 h in mouse erythrocytes. In mouse plasma, imexon treatment led to a significant decrease in cystine levels 2-4 h after drug administration. Notably, by this time, free imexon plasma levels were nondetectable. By investigating the pharmacokinetics of imexon, we also found that imexon undergoes rapid clearance from plasma in a dose-independent fashion with a half-life of 12-15 min. In summary, imexon is active against several cancer types in vivo. Imexon also decreases circulating thiols and exhibits dose-independent pharmacokinetics in mice. Plasma cystine levels may represent a biomarker of imexon activity in vivo.

Original languageEnglish (US)
Pages (from-to)1179-1184
Number of pages6
JournalAnti-Cancer Drugs
Volume17
Issue number10
DOIs
StatePublished - Nov 2006

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Pharmacokinetics
Sulfhydryl Compounds
Cystine
Maximum Tolerated Dose
Biomarkers
4-imino-1,3-diazabicyclo(3.1.0)hexan-2-one
Neoplasms
Phase II Clinical Trials
Clinical Trials, Phase I
SCID Mice
Intraperitoneal Injections
Heterografts
Glutathione
Half-Life
Reactive Oxygen Species
Appointments and Schedules
Erythrocytes
Pharmacology
Cell Line

Keywords

  • Biomarkers
  • Imexon
  • Pharmacokinetics
  • Thiols
  • Xenograft

ASJC Scopus subject areas

  • Pharmacology
  • Cancer Research
  • Oncology

Cite this

Preclinical antitumor activity, pharmacokinetics and pharmacodynamics of imexon in mice. / Pourpak, Alan; Meyers, Ross O.; Samulitis, Betty K.; Chow, Hsiao-Hui; Kepler, Carole Y.; Raymond, Mary A.; Hersh, Evan M; Dorr, Robert T.

In: Anti-Cancer Drugs, Vol. 17, No. 10, 11.2006, p. 1179-1184.

Research output: Contribution to journalArticle

Pourpak, Alan ; Meyers, Ross O. ; Samulitis, Betty K. ; Chow, Hsiao-Hui ; Kepler, Carole Y. ; Raymond, Mary A. ; Hersh, Evan M ; Dorr, Robert T. / Preclinical antitumor activity, pharmacokinetics and pharmacodynamics of imexon in mice. In: Anti-Cancer Drugs. 2006 ; Vol. 17, No. 10. pp. 1179-1184.
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