Combining low-dose difluoromethylornithine (DFMO) and the nonsteroidal anti-inflammatory drug (NSAID) sulindac lowers the risk for recurrent colorectal adenomas.
The results of the phase 3 randomized trial, which were reported here at the American Association for Cancer Research 2008 Annual Meeting, showed that among patients who received the active drug combination, there was a 70% decrease in all adenomas and a 92% reduction in advanced adenomas. A 95% reduction in multiple adenomas was also observed.
“There has been evidence for some time that preventing colon cancer by chemical means with the use of drugs is possible, based on animal studies and those done in vitro in the test tube,” lead author Frank Meyskens, MD, director of the Cancer Center at the University of California at Irvine, told journalists. “However, translating this sort of information into clinical benefit is very high risk and a long-term proposition.”
Polyamines are aliphatic amines that regulate cell division and proliferation and are involved in the differentiation of many tissues. They have also been considered a promising target for cancer therapies and, in a number of preclinical organ site models, DFMO decreased the rate of adenomas and cancers by lowering intracellular levels of polyamines. DFMO is an enzyme-activated irreversible inhibitor of ornithine decarboxylase, the first enzyme in polyamine synthesis, which decreases polyamine levels by inhibiting the initial step in the polyamine synthesis pathway.
“Polyamines are also obtained from the diet and, in the American diet, they most commonly come from orange juice, in terms of quantity,” said Dr. Meyskens. “Meat has a high quantity of polyamines as well.”
DFMO was synthesized several decades ago and has been approved for the treatment of African trypanosomiasis. The hearing loss that has been seen at very high doses is reversible; at low doses, there is no significant audiotoxicity. “It is subclinical,” said Dr. Meyskens. “It is very subtle, and the patients do not notice it.
Dr. Meyskens and colleagues conducted a series of pilot studies from 1989 to 1997 to determine the lowest dose of DFMO that could be given and still be effective in lowering the polyamine level in the flat mucosa of the colon. They established a dose that was 1/50 of what would usually be used to treat advanced cancers.
“We decided back in the late 1980s that we were going to take a different approach to chemoprevention,” he said. “Any drug that we were going to develop would be utilized at the lowest dose possible. Second, we recognized from animal studies that we would have to use it in combination so as to be able to increase the efficacy of both drugs while decreasing the side effects.”
For a variety of reasons, the researchers decided to combine DFMO with the NSAID sulindac. In the current study, they evaluated the combination of low-dose DFMO and sulindac in 375 patients who had a history of at least 1 colorectal polyp within the previous 5 years. The cohort was randomized to receive either a combination of 500 mg DFMO daily plus 150 mg sulindac or placebo. Based on the recommendation of the Data Safety and Monitoring Board, they conducted an accelerated second analysis after 70% of patients had completed their 3-year or off-study colonoscopy; at that time the study was ended.
Overall, a highly significant reduction in all adenomas was observed (70%), as was a reduction in advanced adenomas (92%) and multiple adenomas (95%). These results were comparable to data observed in animal studies. In biopsies taken of adjacent rectal mucosa, putrescine and spermidine levels were also markedly decreased among patients who had received the combination drug therapy at both 12 and 36 months. There was also a significant correlation between reduced levels of polyamines and the recurrence of adenomas.
Prostaglandin E2 levels remained unaffected by the therapy, although the researchers noted a trend toward a correlation between decreased levels and adenoma recurrence. They hypothesize that this was most likely caused by an independent action of sulindac.
This therapeutic combination of agents might also be useful in other patient categories. “Patients who have been shown to have advanced adenomas are probably the largest group that will be helped,” he said. “Another group consists of those who have been cured of colon cancer, because about 35% will go on to have another colon cancer, so they are a good target.”
American Association for Cancer Research (AACR) 2008 Annual Meeting: Abstract LB-142. Presented April 14, 2008.
Reviewed By Dr. Ramaz MItaishvili
