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Rationale for, and design of, a clinical trial targeting polyamine metabolism for colon cancer chemoprevention

E W Gerner1, F L Meyskens, S Goldschmid

  • 1Arizona Cancer Center, Department of Cell Biology and Anatomy, The University of Arizona, Tucson, AZ 85724, USA. egerner@azcc.arizona.edu

Amino Acids
|March 31, 2007
PubMed

Insights

Difluoromethylornithine (DFMO) and NSAIDs like sulindac show promise in preventing colon polyps. This combination therapy arrests growth in cell models and suppresses intestinal cancer in mice, supporting human trials.

Area of Science:

  • Oncology
  • Gastroenterology
  • Pharmacology

Background:

  • Polyamine metabolic genes are frequently altered in colon adenomas and cancers.
  • Inhibitors of ornithine decarboxylase (e.g., DFMO) and NSAIDs targeting polyamine metabolism show additive effects in preclinical models.
  • These findings support the investigation of combined DFMO and NSAID therapy for colon cancer prevention.

Purpose of the Study:

  • To evaluate the efficacy and safety of combining DFMO and sulindac for colon polyp prevention.
  • To assess the impact of this combination on colorectal tissue polyamine and prostaglandin E2 levels.
  • To establish a basis for a larger Phase III clinical trial.

Main Methods:

  • A Phase IIb clinical study was conducted comparing DFMO plus sulindac against a placebo.
  • Key endpoints included colorectal tissue polyamine and prostaglandin E2 levels, and participant toxicity.
  • The study design served as a vanguard for a subsequent randomized, placebo-controlled Phase III trial.

Main Results:

  • Preclinical studies demonstrated additive growth arrest and cancer suppression with DFMO and NSAIDs.
  • The Phase IIb study's design and endpoints informed the protocol for the Phase III trial.
  • Seventy percent of participants in the Phase IIb study were nearing completion of three years of treatment by December 2006.

Conclusions:

  • The combination of DFMO and sulindac is a promising strategy for colon polyp prevention.
  • Further investigation in a large-scale Phase III trial is warranted.
  • This therapeutic approach targets key pathways in colorectal carcinogenesis.

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