Amino Acids

, Volume 33, Issue 2, pp 189–195

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

  • E. W. Gerner
  • F. L. MeyskensJr
  • S. Goldschmid
  • P. Lance
  • D. Pelot
Review Article

DOI: 10.1007/s00726-007-0515-2

Cite this article as:
Gerner, E., Meyskens, F., Goldschmid, S. et al. Amino Acids (2007) 33: 189. doi:10.1007/s00726-007-0515-2

Summary.

Polyamine metabolic genes are downstream targets of several genes commonly mutated in colon adenomas and cancers. Inhibitors of ornithine decarboxylase, such as difluoromethylornithine (DFMO), and agents that stimulate polyamine acetylation and export, such as non-steroidal anti-inflammatory drugs (NSAIDS), act at least additively to arrest growth in human cell models and suppress intestinal carcinogenesis in mice. These preclinical studies provided the rationale for colon cancer prevention trials in humans. A Phase IIb clinical study comparing the combination of DFMO and the NSAID sulindac versus placebo was conducted. Endpoints were colorectal tissue polyamine and prostaglandin E2 contents and overall toxicity to participants. Participants in the Phase IIb study served as a vanguard for a randomized, placebo-controlled prospective Phase III trial of the combination of DFMO and sulindac with the primary study endpoint the prevention of colon polyps. Seventy percent of participants will have completed the three years of treatment in December 2006.

Keywords: Colon cancer – Chemoprevention – Polyamines – Difluoromethylornithine – Nonsteroidal anti-inflammatory drugs – Clinical trials

Abbreviations:

APC

Adenomatous polyposis coli

COX1

cyclooxygenase 1

COX2

cyclooxygenase 2

DFMO

difluoromethylornithine

FAP

familial adenomatous polyposis

HNPCC

hereditary non-polyposis colon cancer

NSAIDS

non-steroidal anti-inflammatory drugs

ODC

ornithine decarboxylase

PPARγ

peroxisomal proliferator activated receptor γ

SAT

spermidine/spermine N1-acetyltransferase

SNP

single nucleotide polymorphism

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • E. W. Gerner
    • 1
  • F. L. MeyskensJr
    • 2
  • S. Goldschmid
    • 3
  • P. Lance
    • 3
  • D. Pelot
    • 2
  1. 1.Arizona Cancer Center, Department of Cell Biology and AnatomyThe University of ArizonaTucsonUSA
  2. 2.Chao Family Comprehensive Cancer Center, Department of MedicineThe University of CaliforniaIrvineUSA
  3. 3.Arizona Cancer Center, Department of MedicineThe University of ArizonaTucsonUSA