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.
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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
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Gerner, E., Meyskens, F., Goldschmid, S. et al. Rationale for, and design of, a clinical trial targeting polyamine metabolism for colon cancer chemoprevention. Amino Acids 33, 189–195 (2007). https://doi.org/10.1007/s00726-007-0515-2
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DOI: https://doi.org/10.1007/s00726-007-0515-2